Public Project Description:                 

CREATE is a global research and implementation project targeting tuberculosis (TB) control in areas with severe HIV/AIDS epidemics. CREATE’s purpose is to evaluate novel strategies to reduce TB morbidity and mortality in populations with high rates of HIV and TB co-infection. TB is the leading killer of people with HIV infection worldwide, and the HIV epidemic has seriously undermined TB control efforts globally. New strategies using currently existing tools will enhance TB control and will facilitate future interventions designed to reduce the incidence of morbidity and mortality from HIV-related TB.

CREATE is conducting three large, community level studies evaluating alternative strategies for control of TB in Brazil, South Africa and Zambia.  The Thibela TB project is assessing the impact of community-wide isoniazid (INH) preventive therapy (IPT) in South African miners.  The THRio study is evaluating extensive use of IPT in HIV-infected patients with access to antiretroviral therapy in Rio de Janeiro.  The ZAMSTAR study is a community-randomized trial of enhanced TB case finding and household interventions to reduce risks among contacts of TB patients in Zambia and South Africa.

CREATE has a Biostatistics Core at the Johns Hopkins Bloomberg School of Public Health and the London School of Hygiene and Tropical Medicine.  The CREATE Policy and Advocacy Core is shared by the Administrative Core, the World Health Organization and each of the individual projects.  The Core maintains communication with the TB/HIV global community, and advocates policies to improve TB/HIV control at the local, national and global levels.  An Education and Training Core provides support to study sites for training a new generation of public health researchers who will have an enduring impact on health improvement in the years to come.  A Modeling Project is using data collected from

CREATE studies and other research to determine the impact of scale-up of population level interventions for TB/HIV throughout the regions of the world where these twin epidemics are prevalent.     Activities focused on promoting the deliverability of interventions for TB/HIV are conducted at the global level by the Administrative Core and within each of the partner countries by study teams.         

 

Introduction  

The Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) is a global health research and policy/advocacy consortium with the goal of identifying, evaluating and advocating for novel strategies to reduce tuberculosis incidence in populations with high rates of HIV and tuberculosis co-infection.  CREATE is coordinated by the Johns Hopkins Center for Tuberculosis Research and has multiple international partners.  This report provides a summary of activities for year 5, from 1 September 2008 through 31 October 2009, the new year-end date based on the supplemental award received in 2008.  This report contains summaries of major achievements, progress and challenges with the CREATE studies and policy/advocacy work, along with activities tables showing progress with specific objectives and detailed budgetary information.  An organizational chart for CREATE is presented below.

 

Figure 1.  Organizational chart of the CREATE consortium.

 

GENERAL PROGRESS

CREATE has had a highly successful year, beginning with the receipt of $32 million in supplemental funds from the Bill and Melinda Gates Foundation that will allow all of the studies to continue through completion and measurement of primary and secondary endpoints.  The revised work plans submitted last year are all on target, and the studies will meet their ambitious goals within the timelines specified in last year’s submission.  CREATE’s cores are also all on target in achieving their goals and objectives, with the Policy and Advocacy Core making major strides in promoting awareness of TB/HIV control issues both globally and within the CREATE partner countries, and in stimulating changes in policy and practice on the ground.  The newest mandate of CREATE, the development of a detailed Deliverability Plan for assuring the implementation of the interventions being tested by the consortium, is well underway and has resulted in global and local partnerships with policy, funding and implementing entities in the TB and HIV arenas. 

Scientific productivity from the CREATE projects has been particularly strong in the past year.  The ZAMSTAR project has published baseline prevalence data on TB and HIV infection in Zambia, documenting the heavy burden of disease in both rural and peri-urban populations and underscoring the rationale for the interventions being used.  The Thibela study has presented important data on the lack of selection for INH resistance in participants who develop TB after receiving IPT.  The THRio study has published an analysis of the high rates of recurrent TB in HIV-infected individuals, suggesting that secondary IPT may be necessary and beneficial as a control strategy.  Finally, the Cores have also produced high-impact new research on controlling HIV-related TB.  The Modeling project has published papers in the past year addressing the role of culture and drug susceptibility testing in controlling MDR and XDR TB in South Africa and the limitations of case detection as a means of reducing TB incidence.  CREATE is also playing a leading role in international scientific meetings, co-sponsoring TB/HIV symposia at the World Lung Health Conference, the Conference on Retroviruses and Opportunistic Infections and the International AIDS Society meeting.  CREATE is producing data, informing policy and advocating for changes in measures used at the clinical and public health levels in high burden settings and is accomplishing the goals and objectives laid out in its original and revised research and activity plans.

 

Specific Results

 

 

Accomplishments

Objective 1:  To develop, evaluate, and promote new public health strategies to reduce the incidence of tuberculosis in settings of high HIV prevalence.

Overall Goal:  As noted above, CREATE is a global research and implementation project targeting TB control in areas with severe HIV/AIDS epidemics.  The goals of the three projects follow.  The Thibela TB project aims to reduce TB incidence by providing isoniazid preventive therapy (IPT) to South African miners.  The THRio study is evaluating extensive use of IPT in HIV-infected patients with access to antiretroviral therapy in Rio de Janeiro.  The ZAMSTAR study is a community-randomized trial of enhanced TB case finding and household interventions to reduce the prevalence of TB and HIV in Zambia and South Africa.

A summary of the studies’ primary and secondary aims, target dates for completion of primary analyses and most recent power calculations for the primary goals is given below.

	Thibela	THRio	ZAMSTAR
Primary endpoints	1.     1. TB incidence in the final 12 months of follow up	1. Measured incidence of active TB in the HIV clinic population before and following implementation of IPT policy. 2. Comparative impact of IPT and ARVs on TB incidence in the HIV clinic population	1. Prevalence of positive cultures for M. tuberculosis from respiratory samples from a random sample from 5000 adults in each of the 24 ZAMSTAR communities.
Secondary endpoints	1.     TB case notification rates during the 24-40 month follow-up period after enrollment. 2.     Trends in TB case notification rates in sequential 6-month time periods following the enrollment of the intervention and control clusters. 3.     TB prevalence at the end of the follow-up period. 4.     All-cause mortality during the 24-40 month follow-up period. 5.     Case notification rate of isoniazid-resistant TB (among individuals with no prior history of TB). 6.     Safety of community-wide IPT.	1. Characteristics of TST+/HIV-infected patients. 2. Clinical, demographic and laboratory predictors of developing active TB 3. Lessons learned related to training and implementation	1. At community level: Incidence of tuberculosis infection in children TST negative at baseline. Tuberculosis treatment outcomes measured by cohort analysis of strengthened tuberculosis register data. Additional tuberculosis cases detected by ECF and HH measured using the strengthened laboratory register. Uptake of HIV testing and counseling and uptake and adherence to tuberculosis preventive therapy measured using the testing and counseling register. Costs of each component of the intervention and cost-effectiveness comparisons of strategies to find and prevent cases of tuberculosis and HIV. 2. At household level: (measured on a cohort of households) Cumulative HIV incidence among those >14 years old. Tuberculosis treatment outcomes measured by cohort analysis of strengthened tuberculosis register data Uptake of HIV testing and counseling and uptake and adherence to tuberculosis preventive therapy measured using the testing and counseling register Tuberculosis transmission within the household measured by TST conversion in children and the Quantiferon-Gold In Tube conversion in adults. Cumulative incidence of tuberculosis Stigma levels
Dates for ascertaining primary endpoints	The primary endpoint will be measured from February 2008 to February 2011 due to the staggered enrolment of the clusters.  The final culture prevalence survey will be conducted from June 2009 to June 2011	Data are collected continually from the outset of the project.  Final data collection will be completed by August 31, 2010.	Prevalence surveys will run from October 2009 until December 2010.  Analysis will commence in 2011.
Power for primary endpoints	In 2008, accrued data indicated Thibela TB would have 80% power to detect 40% effectiveness, an improvement over the initial sample size calculations that indicated only a 60% reduction in TB incidence could be detected.  Further improvements in recruitment and adherence may lead to increased power.	The change in primary endpoint restricts the analysis to those eligible for the intervention (about 72%) who actually show up in a clinic (loss of about 15% of person-years). These two countervailing effects leave the powerabout the same: 58% for a 25% reduction in TB incidence, but achieving a 25% reduction is more likely in this analysis group.	For the primary outcome of TB prevalence, nothing has changed in terms of power of presumed effect of the intervention.  Based on baseline prevalence survey and process data, ZAMSTAR is still expected to be able to detect a 30% reductionin TB prevalence with 80% power, with a control prevalence of about 1%.

THRio: The THRio study is a phased implementation study of tuberculin skin testing and IPT in 29 HIV clinics in Rio de Janeiro, Brazil.  The two main objectives of the study both relate to TB incidence in the HIV clinic population. The first will compare incidence of active TB in those clinics that have received training and implementation of the IPT policy to those that have not. The second is to assess the comparative impact of IPT and ARVs on TB incidence.

The study team has successfully implemented the primary intervention strategy in all 29 HIV clinics.  Every two months, over the course of 29 months, the HIV and TB staff at two clinics was trained, with separate sessions for clinicians, nurses, and support staff.  The study was described in detail, focusing on the timeline of events and the importance of adhering to the TB protocols, with emphasis on IPT.  Materials covered in the training sessions included the rationale for the policy, pathogenesis of TB, diagnosis of latent and active TB, TB preventive therapy and monitoring of patients receiving INH.  Instructions for documenting tuberculin skin tests (TSTs) and IPT using TB preventive therapy flow sheets and log books were given to nurses, physicians and supervisors. It is clear from preliminary analyses that the number of patients receiving TST’s and IPT has significantly increased in clinics post-intervention and that patients received the interventions more quickly.

Study outcomes are being captured through regular extraction of information from individual patient records at each clinic. Following baseline visits to all study clinics prior to intervention, data abstractors visit study clinics on a regular schedule to review patient charts for study outcomes and to complete the forms, which collect data on: new patient registration, baseline evaluation for new patients, including TSTs, CD4, viral load, opportunistic diseases with emphasis on TB, HAART history and IPT data.  Interval data abstractions follow the same strategy, looking at the same variables previously mentioned.  Data abstraction has been ongoing throughout and each clinic has had at least four abstraction visits and all collected data has been entered into the study database.

Process data from the study are shown below in two Kaplan-Meier plots of time to TST and time to IPT for TST-positive individuals.  The results clearly show that the intervention has been highly effective in increasing the uptake of both TST and IPT in the clinics, though challenges remain.

 

Figure 2.  Time from first clinic visit to TST reading in TST-eligible patients in the THRio clinics, before and after intervention.  Delays in obtaining TST post-intervention, though much shorter than prior to the intervention, persist, and relate to the timing of clinic visits and clinical effectiveness of policy.

 

Figure 3.  Time from positive TST to initiation of IPT, before and after intervention.

 

The overall incidence of TB in the THRio clinics remains high, with a rate of 2.4 cases per 100 person years.  Incidence is lower in individuals taking HAART than in those not on HAART at 2.1 vs. 3.7 cases per 100 person-years.  Of note and importance, of the more than 1200 cases of TB that have occurred during the THRio study, approximately 500 were diagnosed on entry into the clinics, meaning that preventive measures were not possible.  Analyses by IPT use have not yet been performed.

At the CREATE Data Safety Monitoring Board meeting in June 2009, three comments regarding the THRio study were included in the final report.

1. The DSMB is concerned about analysis of THRio’s impact and recommends the vertical approach to analysis.
2. The DSMB is also concerned about the relatively low rate of lab confirmation of TB in Rio and high reliance on clinical diagnosis. Dick Chaisson pointed out that diagnosis in Brazil also relies on X-ray, per health department protocols there.
3. The DSMB acknowledges that the studies are being done in real-life situations, so they have the messiness of real life.

With respect to the analysis, the Biostats Core had considered a number of approaches and presented these to the DSMB.  All agreed, however, that the vertical approach was preferred.  Revised power calculations for this approach were made in the 2008 report, and these have not changed.  The study is now able to detect a 40% reduction in TB incidence following the intervention with 67% power.

Regarding TB diagnoses, the Brazilian health care system has historically relied heavily on chest x-rays for detecting TB, rather than microbiologic confirmation.  We have endeavored to change this through the MGIT project, and have now collected sputum specimens for >500 patients with suspected TB using this approach.  However, during the course of the study many diagnoses have been made radiologically.  The table below shows the distribution of types of diagnoses for the 853 TB cases for which data collection is complete.  Please note that this includes both pulmonary and extrapulmonary TB cases.  This information will be shared with the DSMB.

 

Table 1.  Method for diagnosing TB in the THRio study.

Total # TB Cases	1365
Total # with TB form completed	853
Smear +	208 (24%)
Culture + only	49 (6%)
CXR + only (no sputum or – )	473 (55%)
Clinical diagnosis only	76 (9%)

Thibela TB: Thibela TB has made significant progress with more than 27,400 individuals having consented to the study. Furthermore, Thibela TB has inspired the South African Government, companies and other organizations to take action against TB. Thibela TB investigators have contributed to informing international, national and industry policy on TB/HIV issues and advocating for isoniazid preventive therapy (IPT). The project’s overall progress against objectives is good.  Progress, challenges, preliminary results, ancillary studies and outputs are described as is a projection of future issues related to the completion of the study.

As of 31 March 2009 the baseline prevalence survey was completed in all 15 clusters. A total of 15,638 participants have been enrolled. The proportion of miners that reported being treated for TB previously was 11.7% and varied substantially by cluster (range 7.4% to 16.2%). A total of 293 participants (2%) were currently on TB treatment at the time of the survey. IPT use was low with less than 1% of participants reporting current or prior isoniazid use. ART use (current and prior combined) ranged from 0.9% to 4.4% by cluster.

As of 31 March 2009 27,420 participants had consented to the study and were evaluated for IPT.  All eight intervention clusters have started enrolment. As of June 2009, all eight intervention clusters have completed the “main recruitment phase” and three have also completed the “new recruits phase.”

Of these 27,420 participants, 24,059 (87.7%) were eligible for IPT and so 23,585 of 41,697 employees and contractors have started IPT, representing 56.6% of the workforce in intervention clusters. This varies across clusters (Figure 4) with more recent clusters demonstrating higher uptake.

 

Figure 4: Time trends in the percentage of miners enrolling at five intervention shafts

Retention of participants is an important process measure in Thibela TB. Data on time to drop-out are presented here for the first seven intervention clusters that have initiated enrolment as of 1 December 2008, in order to ensure follow-up of at least four months. Drop-out is defined as loss to follow-up (more than 90 days late for a follow-up visit); left study due to suspected AE/TB suspect; left study of own accord; left workforce or died. Figure 5 shows Kaplan-Meier plots of time to drop-out from the study for the seven clusters. Follow-up has finished for all participants in clusters I2, I4, I6 and I8.

 

Figure 5: Kaplan-Meier curves of time to drop-out from the Thibela TB study, by mine shaft, for all participants who were ever dispensed isoniazid.

Data are also reported as the proportion of “eligible” participants who received 180 days of isoniazid, generally considered to provide an effective dose of isoniazid. Analysis is restricted to “eligible” participants defined as having been dispensed INH on at least 6 occasions. There is considerable variation across clusters (35.1%-73.9%) though some trend for better adherence for clusters recruited more recently.

Adherence to isoniazid is measured by self-reported time of last dose, number of doses taken in last 3 and 14 days and pill count from returned INH packaging. The percentage who reported missing no doses in the last 3 days was high (91.9%) at all visits and in all five shafts for those who arrived for their scheduled follow-up visit on time (always >85%).

A total of 126 suspected adverse events (AEs) have been reported; 14 (11%) hepatitis, 49 (39%) peripheral neuropathy, 60 (48%) hypersensitivity rash and three (2%) participants with convulsion. The majority were graded as either mild (66%) or moderate (31%). Two hepatitis cases were graded as severe and one convulsion event was recorded as life threatening. Four of the 126 events were coded as serious; three hepatitis cases and one convulsion.  Overall 87% of the suspected AEs were graded as possibly related to isoniazid, 10% probably or definitely related and 3% not related.

The final prevalence survey (FPS) was initially piloted at one cluster in the Carletonville region in April-May 2009. The recruitment strategy was based on inviting randomly selected miners to take part in study and where this initial invitation took place at the mine “crush” following the end of their shift. After piloting for 2 weeks it was apparent that uptake was poor with only 26% of selected miners, at first invitation, consenting to the study. This low uptake was primarily due to two reasons: immediate refusal to be part of the study and the team being unable to contact the selected miner due to, for example, being on leave or working a different shift than what was expected. As a result of this experience and following an extensive review of alternative options for recruiting at different sites a second pilot was initiated in the same region in June 2009. This pilot took place at the mine occupational health clinic where miners attend for their annual fitness examination. The pilot has shown that recruitment to the FPS has vastly improved with 100% of selected miners consenting to the study. It is envisaged that the recruitment strategy to the FPS will be revised and will now take place at mine occupational health clinics.

There have been no changes to the statistical assumptions of the Thibela study, and the rates of enrollment, retention and participation in the final prevalence survey give us greater confidence of achieving the primary endpoints.

Recently, Thibela reported on TB cases occurring after exposure to IPT. Between July 2006 and February 2009 126 such cases were identified among 23095 who started IPT. 94/126 were first TB episodes and the median time from IPT start to TB treatment start was 316 days. 89% of those with known HIV status were HIV positive, with a median CD4 of 196 (N=51). Among 84 with adequate follow up time to assign a treatment outcome, 37 (44%) were cured, 24 (29%) completed treatment, 8 (10%) died and only 1 (1.2%) was documented as having treatment failure.  Among 58 first TB episodes after IPT, 7 (12.1%) had any isoniazid resistance and 1 (1.7%) had MDR. This compares with a background isoniazid resistance rate of about 10% among first episodes. Overall these results suggest no excess of isoniazid resistance among cases occurring after IPT. These data were presented at the IAS conference in Cape Town in July 2009, and the abstract was awarded the first IAS TB/HIV research prize.

No concerns about the Thibela study were relayed during the recent DSMB meeting.

 

ZAMSTAR: ZAMSTAR continues its interventions in 24 communities in Zambia and South Africa.  Enhanced case finding (ECF) and household interventions (HH) to find and treat TB and HIV are implemented in a factorial design.  Progress in meeting implementation objectives has been excellent in all communities.  To date, 1239/5920 (22%) smear positive TB cases in the 12 ECF communities were found via ECF activities, in line with modeling for having the predicted impact of a 30% reduction in prevalence.  Uptake of HIV testing in HH intervention rising over time – up to 85% of adults accepting HIV testing in some communities. The study is on track and keeping to most major milestones

National policies for TB/HIV are changing in both countries, and ZAMSTAR has contributed as follows:

• INH now being procured for IPT via GDF via Zambian MoH
• VCT registers in SA include ICF indicators
• TB registers in both SA and Zambia include HIV test data
• National Infection Control policy drafted with support from ZAMSTAR in Zambia
• Expansion of culture through mobile laboratories approved by Zambian MoH

 

Greater involvement of Ministries of Health with TB research has also been achieved in both countries.  In South Africa, the first framework for TB research priorities has been produced with ZAMSTAR input.  In Zambia, the ZAMSTAR team is involved in planning for a national TB prevalence survey to be done in collaboration with the WHO as a follow on to the study prevalence surveys.  Additionally, the ZAMSTAR team is conducting national drug resistance survey in Zambia with funding from the Global Fund for AIDS, TB and Malaria (GFATM).

Other stakeholders are taking up ZAMSTAR interventions and preparing to scale them up.  Fast-track/open access sputum labs and ECF is being used throughout Cape Metropole and in several new Zambian districts.  HH interventions have been integrated into Home-based care teams in Zambia.  Roll-out plans for IPT in Western Cape Province are being developed with PEPFAR funding and ZAMSTAR leadership.  Study results are being disseminated through publications, conference presentations, and engagement with policy makers.

Study procedures and processes are functioning smoothly.  We have completed quality assurance procedures in 24 communities, completed recruitment for the secondary outcome cohorts 1 (SOCS1) and will began recruitment for SOCS2 in August 2008.  Losses to follow-up were higher than anticipated, but the cohort will include those found at SOCS3 who were not found at SOCS2, so total follow-up will be better than SOCS2 figures suggest.  Recruitment for the TST follow-up survey started May 2009 and is proceeding well.  Dissemination of process data and baseline data to all South African communities has occurred as planned, and transition meetings with district management teams and stakeholders are underway.  Sensitization of communities for the final prevalence surveys and ongoing TST surveys is being pursued through multiple venues and communications strategies, tailored to local needs.  In preparation for the final prevalence surveys we have submitted all Ethics approvals, developed detailed SOPs, refurbished the study laboratory in South Africa and designed and ordered 4 mini-labs for Zambia.  We are discussing with MoH and stakeholders how best to use the minilabs in the future following the study.  Additional work for the surveys includes re-mapping and census details for sampling, ordering sourcing and procuring supplies, finalizing questionnaires and additional studies, and finalizing protocols.

The DSMB had no specific feedback or comments for the ZAMSTAR study team at its recent meeting.

 

Modeling Project: The Modeling Project was approved and funded in Year 4, but is one year behind schedule owing to a number of logistical and scientific issues.  The most important of these is that the project was initially designed to mesh with the original timelines of the Thibela and ZAMSTAR studies.  As these were both delayed in Years 3 and 4, data needed for modeling work has been delayed.  In addition, personnel changes at the London School of Hygiene and Tropical Medicine and the relocation of Dr. Emilia Vynnycky to the Health Protection Agency also slowed work.  The Project has accelerated activity this past year and is now well along with its first objective.  We anticipate fully meeting our objectives over the course of four years. 

 

The original aims of the project were:

1.     To develop models that fit baseline epidemiologic data on TB and HIV from the CREATE trials, ZAMSTAR and Thibela TB, and data from African populations with differing TB/HIV epidemic characteristics.  Data from two trials with designs and aims complementary to ZAMSTAR and Thibela TB will also be included: the ongoing DETECTB trial in Zimbabwe and the community-wide preventive therapy trial from 1957 in Bethel, Alaska.^1-3    

2.     To investigate key model assumptions through additional fieldwork in Southern Africa. 

3.     To finalize and validate models in parallel with trial interventions, to enable timely modeling, projection, and in-depth understanding of the CREATE trial results, in turn increasing the impact of  trial outcomes through better communication to policy-makers of the likely short- and long-term impact of adopting similar strategies in other populations. 

 

This year’s activities have focused on 4 of the main modules of the simulation model:

1.             Parameterizing the distribution of latent TB infection (LTBI): calibration using TST and IGRA results (populating the microsimulation model).

2.             Demographic modeling of the DETECTB population (populating the microsimulation model)

3.             Modeling combined interventions against HIV (modeling the HIV epidemic and combined HIV interventions, including ART).

4.             Starting the TB dynamic modeling, using a Deterministic model for DETECTB.

 

 1. TST calibration using IGRA results.

The goal is to inform the interpretation of TST results from the HIV/TB prevalence surveys of DETECTB, where age, HIV and TST results are available for a random selection of the adult population under study.  The relevance of this work to the larger project is in parameterizing models: LTBI prevalence is an important input to simple deterministic models; and fitting measured LTBI patterns by age, gender, and household will be

a)     an important check of the validity of assumptions underlying microsimulation models

b)    Have a major impact on model output and the estimated impact of different control measures

 

Naïve interpretation of TST results in this setting is complicated by the relatively high HIV prevalence (HIV+ individuals being more likely to be skin test anergic), and the large amount of cross-reaction due to high rates of non-specific tuberculin sensitivity in Zimbabwe (as in Zambia but not in Cape Town). Statistical distributions were fitted to the TST response histograms stratified by ELISpot and HIV result, and the TST results for the DETECTB population were then fitted as a mixture of the relevant distribution by HIV-status. This allowed a prediction of the probability that given individuals would have tested positive to ELISpot by HIV status.  Unfortunately, plausible outputs have not been obtained with this method, with implausibly low estimates for the likely significance of high TST values. 

From the data available it is not clear if this is solely due to waning of ELISpot responses (test dynamics), or from population differences between the target (TST only) and calibration (TST and ELISpot) populations although they were both from Harare.  ZAMSTAR IGRA/TST data collected under the FIND initiatives will be available to the modeling team within the next few months and may circumvent these calibration problems.

 

2. Demographic modeling of the DETECTB population and baseline data.

The goal is to provide a realistic statistical model of population structure from available data, using simplifications that reduce the required input variables to a minimal set.  The relevance is in understanding of the clustering of TB infection by household and allowing data-driven generation of synthetic populations that match these important characteristics.  This has been approached by modeling the conditional distributions of different variables (e.g. the probability there are 2 women in a household given the presence of 2 men), given the likely relevance of pair-structure to disease transmission and household-based tracing interventions. Satisfactory models have been developed to characterize household sizes, age distributions for men and women, household sizes by gender, and age pairings by household. 

We have also developed a novel approach to defining what range of dynamics at the level of the household is compatible with the observed patterns. That is, given mortality and fertility patterns and historical HIV prevalence by age, what range of household change rates and emigrations/immigration yield the observed distribution as a (quasi) equilibrium? This takes into account movement of individuals that may make their current household environment unrepresentative of their past exposure history. Secondly, this provides the basis for realistic assumptions of household dynamics.  We have master equations that describe the evolution of the statistical distributions describing the population under the specified demographic changes. Solving (possibly approximately) for the equilibrium is still in progress.

 

3. Modeling combined interventions against HIV.

The goal of this work is to derive a model of HIV that can incorporate multiple interventions. The work is based on two sets of theoretical results. The first allows direct computation of equilibrium prevalence and incidence for partial differential equation models with demography and gender and activity levels, which also allow infectiousness and mortality to vary with time since infection. These features are necessary to realistically model the effects of interventions for HIV. The second set simplifies the computation of how measures such as R₀ and the point incidence of infection change under complex, targeted and overlapping interventions, which would naively result in very high-dimensional problems.

 

4. Deterministic modeling for DETECTB.

The goal of this work is to provide a crude framework to aid interpretation of the results from DETECTB and to initiate the TB modeling component. Particular questions are:

• Accounting for the differential reductions in active TB prevalence in HIV positive and negative populations given i) the periodic nature of the DETECTB intervention, and ii) the dramatic regional increase in the incidence risk ratio for TB given HIV, likely to be connected with the aging of the HIV epidemic
• Projecting the effects on TB prevalence of continuing the DETECTB intervention vs. stopping.

These are being approached with a minimalist model of HIV/TB in terms of ordinary differential equations. The work so far has centered on parameterizing the model with estimates from literature, and in developing approximations to allow parameters specific to the DETECTB population to be extracted from the initial data and trends. The first iteration of the parameterization has been performed, but has yet to be validated and modified.

 

 Changes

Administration Core: Personnel change saw staff turnover in one position, administrative coordinator.  New administrative coordinator is Virginia Kline.

Biostatistics Core: None noted.

Education and Training Core: None noted.

Policy and Advocacy Core:  Andrea DeLuca has left the project to work for the PERCH study, also funded by the Foundation.  Dr. Celine Gounder has been hired to serve as Deliverability Director.  Dr. Gounder is trained in infectious diseases and has spent the last year in Soweto, South Africa, leading a large ICF project for pregnant women with HIV.

THRio: THRio Data Manager Bonnie King left the project and Silvia Cohn joined the project in this capacity.  Ms. Cohn is a native Uruguayan and has >25 years experience in data management and project leadership in HIV cohort studies and clinical trials.

Thibela TB: Leonie Coetzee, Project Director, will leave Thibela TB to join the Global Partnership for Microbicides at the end of September. Project direction will be assumed by Dr. Dave Clark.

ZAMSTAR: Policy, Advocacy and Communications Manager, Justin O’Brien joined staff in Zambia.  Wena Moelich assumed PAC responsibilities, together with new staff member, Amanda Kruger, in South Africa.

Modeling Project: A second post-doctoral mathematician is due to be recruited by Dr Emilia Vynnycky’s group in the Health Protection Agency, London for Major Activity 2.  This has been delayed in order to allow the work to proceed in line with the new timelines for Thibela TB and CREATE. 

 

Challenges

No new challenges were seen in Administration Core, Biostatistics, or Education and Training Cores.

THRio: The primary challenge facing THRio is assurance of proper implementation of the intervention and continued training and re-training of current and new clinic staff.  New clinic staff is trained by the PPD training coordinator as soon as possible after hiring. Re-training of clinic staff through in-clinic training and through regular meetings will help sustain the impact of the intervention.

In order to keep up the intervention and achieving sustainability, the TB program and the HIV/AIDS program of the Rio de Janeiro City Health Department have taken the THRio intervention into their hands and, in a solid TB/HIV integration, are now carrying on the training and the supervision of the TB/HIV activities required by both TB and HIV best practices.   

 

Thibela TB:

Final culture prevalence survey.  The challenge of doing the final culture prevalence survey has been discussed. The new method of recruiting miners from the occupational health service provides an acceptable solution to this problem.

Stakeholder engagement.  Recently, both mine companies and unions are requesting more information about study progress and whether the study is having impact on reducing the incidence of TB. This issue was discussed at the last DSMB meeting. The DSMB approved giving companies data that remained blinded. A feedback to the companies is planned for later in July 2009.

Termination of contracts.  As Thibela TB enters its final stages, contracts of employment are coming to an end, which is causing staff anxiety, particularly in the current financial crisis when it is more difficult to find other jobs. The recently appointed human resource director, Mrs. Shariffa Miller, is implementing an HR plan to support staff during this time and ensure an orderly reduction in Thibela TB staff.

As noted above, Dr Leonie Coetzee, the Thibela TB study director, has now left the project. In the time remaining to complete the study it does not make sense to try recruit and train a new Study director. The roles and responsibilities of Dr Leonie Coetzee have therefore been assigned to the investigators, COO, HR and Finance directors and Thibela TB operational managers, with the COO, Dr. Dave Clark, coordinating the effort.  The investigators will oversee the weekly Ops call and the continued operational implementation of Thibela TB.  This approach has been rolled out over the past month and appears to be working adequately.  In some area, in fact, there have been improvements in management with input from new players.

 

ZAMSTAR:

ZAMSTAR expects to meet its primary objective as stated in the proposal and protocol.  As shown in the table, we still expect to have the same power as originally planned.  The final prevalence surveys are of course a huge challenge, but the logistics, training and planning are now well underway and we are pleased that the threat discussed at the DSMB that the Zambian National Prevalence Survey posed, has now been turned into an opportunity as the delays in the Zambian Ministry of Health have avoided the time clashes and the Zambian National TB program manager is now included as an investigator on our survey.  The Ministry will now benefit from lessons learned during the ZAMSTAR surveys and will hope to be able to use the ZAMSTAR mini-laboratory capacity during the national survey.

For our secondary outcomes there are still some challenges that we are addressing as we go forward.  The follow up TST surveys involve trying to find around 23,000 children, we hope to find 65-70% of the children by visiting their schools and homes and using various strategies in the community.  This will give us adequate power but we will need to explore issues of bias in the loss to follow up.

In the SOCS cohorts, we have found that the death rate is higher than expected in both adults and children and there is more mobility than anticipated.  The HIV seroprevalence is also higher than expected among household contacts.  On the one hand these findings reaffirm the importance of a household based approach to risk for both TB and HIV, but on the other hand they will somewhat reduce our power to detect differences between arms in HIV incidence and TST and QGIT conversion.

Close-out, transition and dissemination to our many stakeholders remain a big task, but we are making new links and spending many hours in discussions with various interested and interesting organizations.

An ongoing challenge is managing the many different tasks with relatively few senior management staff. 

 

Modeling Project:  No challenges are foreseen

 

Lessons Learned

THRio: THRio’s experience emphasizes the continued importance of clinic staff support for the overall project. Without support of clinicians and nurses to order and administer TST and IPT, THRio would be unsuccessful. We have learned that continued information and data sharing with clinic staff at regular meetings helps instill confidence in the intervention and will hopefully result in the sustainability of these practices beyond the life of THRio.

The time to TST testing is significantly improved in all clinics post-intervention; however, the delays remain longer than anticipated. The primary reason for delays is that THRio does not ask patients to come to the clinic for TST and/or IPT, but rather waits for patients to return and offers TST or IPT at that time. While it was anticipated that clinic patients would attend the clinic at least once every 3-4 months, and be approached at that time, we have learned that the time between visits is often longer, with patients sometimes only coming to pick up their ART. Moreover, those patients not receiving ART may have even longer periods between visits. We had hoped that non-ART patients, approximately 20% of our population, would significantly benefit from the intervention. Together, these unanticipated delays may impact the primary outcome of the study as cases and person-time that are allotted to the intervention period are accruing for patients who had no chance of “receiving” a TST or IPT prior to TB diagnosis. However, almost 80% of eligible patients are receiving TSTs at some point after intervention, suggesting that a simple intervention of IPT/TST training can substantially increase the number and proportion of HIV-infected patients receiving TST/IPT.

Thus, while the problem of delayed TST and IPT may reduce the potential impact of THRio, we do not believe that deliverability of TST/IPT beyond THRio will be compromised. Now that the Brazilian government has used the baseline THRio results to strongly encourage HIV clinics throughout Brazil to provide TST/IPT to all HIV clinic patients, we expect uptake to escalate steeply. The goal is to provide all HIV-clinic patients TST/IPT at their next visit. We have done this for a high proportion of patients in THRio, and this would continue to be the goal beyond THRio.

 

Thibela TB: As noted in Thibela TB’s accomplishments, enrollment figures and retention in study are significantly improved in later-enrolled shafts.  The increased recognition of Thibela TB’s contribution to the mining industry, “brand” recognition, and increased staff expertise over time are the major factors in these increases.

 

ZAMSTAR:  Both Household and ECF interventions have proven to be feasible and acceptable to local communities and health systems.  TB-HIV integration has also proceeded more rapidly in the ZAMSTAR sites.  In several of our communities, TB treatment supporters, community advisory boards and their members and health clinic staff have taken the initiative to continue some of the services.   This confirms our belief that these are scalable and affordable interventions.  Beyond the primary and secondary trial objectives, ZAMSTAR is having a wider impact. Many of our 350 staff express the view that ZAMSTAR acts as a bridge between the health service and the community and that they are now seen as a community resource for knowledge on TB and HIV.

As discussed previously, much time needs to be spent working with communities to develop appropriate strategies for both ECF and HH interventions.  This requires careful situation analysis and working within existing resources building links with existing community structures and maintaining close relationships with the district health, education and other services.

 

Modeling Project:  We have anticipated the need for good communication within the consortium, and it has indeed proved essential to hold regular meetings to harmonize thinking between the trial teams and modeling team.

1. Unexpected Results.  No unexpected results have been noted by the three studies.
2. Progress in Achieving a Global Access Strategy.

Note that CREATE’s Deliverability Plan lays out the strategy for the upcoming years.  This plan, submitted in July 2009, will be revised and expanded in accordance with the suggestions of Foundation staff in September 2009.  In addition, the three studies comment as follows.

 

THRio. The Brazilian government has prioritized provision of IPT in HIV-clinics throughout Brazil, based primarily on the THRio study. In late July 2009 the National AIDS Program promulgated a policy requiring HIV clinics to take responsibility for screening patients for active TB and providing IPT to TST positive patients.  The NAP cited the data from THRio in issuing this policy.  Furthermore, the NAP is including IPT and TB drugs in the SICLON, the system that controls HIV drugs (ARVs and OI drugs) nationally. This is an important step because it means that TB prevention and treatment will have the same status, availability, and control in the HIV clinics, nationwide, as all the other medications.  We consider this a major leap forward in TB/HIV activities for the country.

In its partnership with the Global Fund, clinic staffs all over the country have been trained to prevent TB among HIV-positive subjects. In their folders and placards, distributed to state and city health departments wherever they deliver training, THRio’s message “if you have HIV, take the TB test; if you have TB, take the HIV test” is being disseminated. 

Thibela TB. Aurum contributed two data sets to the primary meta-analysis of TB screening in HIV-infected persons. The hope is that the newly recommended TB symptom screening tool will promote intensified TB case finding and increase uptake of isoniazid preventive therapy.  WHO is currently collecting data to inform the revised policy on IPT.  Data from Thibela TB will be used to inform feasibility, advocacy, communication and social mobilization, safety, resistance, adherence, and efficacy.

ZAMSTAR.  As described above, ZAMSTAR is seeing increasing engagement in both countries with both the interventions.  ZAMSTAR has also been invited to join the WHO working group on models of community based HIV testing, building on the experiences gained in planning and implementing the prevalence surveys.

 

Objective 2:  To transform global policies for HIV-related TB through evidence-based advocacy.

 

Below we provide a detailed report on the activities of the Policy and Advocacy Core (PAC), which is responsible for achieving the aims of Objective 2, as well as a more extensive list of objectives developed in 2007.  After discussion with Gates PAC project officer, we are presenting this year’s PAC report in narrative, outlining achievements by the 4 overarching goals delineated in the proposal:  1) successfully concluding the studies, 2) transforming national policies and practice, 3) transforming global policy through advocacy and 4) raising the profile of TB/HIV to advocate for increased funding.  CREATE PAC has increased the breadth and scope of activities in all of these areas in the past year.

 

Overview:  This has been an exciting and productive year for the CREATE PAC.  Collaborations with national and international NGO’s have matured and, as a consequence, a number of activities were implemented to engage and train international advocates and promote 3 I’s policy and implementation. CREATE-Global (CREATE –G) is finding a niche in using its scientific expertise to implement research training for activists internationally, promote community-based research in TB/HIV, and advocate for increased U.S. global TB awareness and funding.

Highlights of the year include the 3I’s satellite Symposium preceding the Annual South African AIDS conference in Durban, the WHO/CREATE symposium “Catalyzing TB/HIV Research” in Cape Town in July 2009,  the  evolving South African advocacy work in MDR/XDR-TB  among miners/migrants, and the significant  involvement with  SA Department of Health (DOH) on government IPT implementation activities.  The CREATE Deliverability Plan is a detailed roadmap that will guide the future global and national activities of the consortium in going beyond policy and advocacy to directly promote implementation of interventions more broadly.

 

Figure 7.  PAC Organizational Chart.

 

Objective 1:   Create and maintain an accommodating environment for conducting and concluding the CREATE studies.

• Crisis communications plans are in effect at all studies and are being used to develop communications plans for dissemination of study results.
• Documenting CREATE Interventions/ Preparing for Dissemination: CREATE-G contracted with James Blue Production Company to develop videos that document the CREATE interventions, demonstrate feasibility of these broad-scale public health interventions and reflect the impact of CREATE on the lives of participants and staff.  The dissemination plan targets Ministries of Health in CREATE study countries, the WHO STOP TB Partnership, PEPFAR implementing partners and TB/HIV NGOs.   Filming is completed in THRio and is near completion in ZAMSTAR and Thibela; videos will be launched at the CREATE annual meeting in October 2009.
• Other CREATE Communications:  The quarterly CREATE PAC Newsletter highlighting CREATE accomplishments is distributed to several hundred organizations. Likewise, the CREATE PAC bulletins are distributed bimonthly to TB/HIV NGO collaborators.  The website continues to be utilized as a TB/HIV resource.
• Staffing Changes: Justin O’Brien was hired as PAC coordinator for ZAMSTAR, Zambia.  Amanda Kruger and Wena Moelich assumed PAC responsibilities for ZAMSTAR, Western Cape.  Andrea DeLuca resigned from CREATE-G.   Lois Eldred, Claudia Costabile and Tim Teeter continue as the CREATE-G PAC team with Celine Gounder, MD, working with policy, advocacy and delivery for CREATE.   Razia Essack-Kauaria resigned as CREATE PAC’s Southern Africa coordinator; CREATE is in the process of reconfiguring this position.   Giselle Israel and Vitoria Vellozo continue with the THRio PAC program; Smanga Nsthele continues to represent Thibela.

 

Objective 2:  Transform national-policies – and practice – for controlling HIV-related TB

• National Press Conferences: Prior to the CREATE annual meeting in Lusaka in September 2008, CREATE held a press conference for Zambian Press on TB/HIV and the need for National Policy on Isoniazid Preventive Therapy (IPT).   Dr. Chaisson, Dr. Ayles, the ZAMSTAR Board President and National TB Control Program Director participated. Two   newspapers and radio picked up the story, but more importantly, the experience highlighted the need for media education on TB and HIV; a Zambian media training conducted in April 2009 created a network of journalists to report on TB, HIV and public health.
• Zambian PAC Advocacy Work:  CREATE and Open Society Institute (OSI) conducted a Zambian PAC Workshop preceding the annual CREATE meeting in Lusaka with 50 representatives of 8 key Zambian NGO’s.  A need for a cohesive advocacy approach to implementing the 3I’s and national IPT policy change was identified.  In April 2009, CREATE, OSI and TAG conducted a Zambian 2 ½ day workshop with 14 national NGOs to follow- up on the identified needs.   A Unified Action Plan for implementing the 3I’s at the national level has been developed as a result of these workshops and trainings.
• Improving Miners Health and Decreasing Cross-Border Transmission of MDR and XDR TB: An open letter to South African Parliament demanding improved safety and health care for SA miners signed by CREATE ARASA, TAC, and other SA advocacy organizations received national press coverage and led to increased pressure to prevent TB in these settings. Thibela has begun formative advocacy work to minimize cross border transmission of MDRTB/XDRTB among miners and migrants; Thibela is working with Lesotho Ministry of Health and the South African Development Corporation.
• Advocacy Work with South Africa Public Sector:  Gavin Churchyard met with the Chief Director of Employee Health and Wellness and his team to adapt the TB/HIV tool kit for the Public Service. TB/HIV activities for the public sector would be implanted as a matter of policy, including the use of IPT CREATE –G and intensified case finding. The workplace TB / HIV tool kit was launched at the Eighth Annual Indaba of the Dept of Public Sector and Administration in November 2008, which was attended by the Minister of Health, Barbara Hogan, and Minister for Public Service and Administration, Mr. Richard Baloyi.

1. Aurum convened a TB Convention in February 2009 on behalf of the Gauteng Department of Health. The aim was to identify gaps in TB/HIV integration. A number of the presentations were given by Aurum staff and included a presentation by Gavin Churchyard on the 3I’s that showcased the Thibela TB project. The convention was well attended and resulted in a formal report with clear recommendations to address the gaps.
2. Aurum is partnering with the department of correctional services to implement TB/HIV activities in prisons.  A TB prevalence survey and evaluation of TB screening using urine LAM have been approved and will commence shortly.
3. Aurum held an update symposium for its workplace and public sector HIV treatment programs in July 2009. One session was devoted to the 3I’s with an emphasis on screening for TB in HIV-infected persons.

• South African Advocacy Work with the Business Sector: Based on the Thibela TB experience, Aurum has been asked to assist Xstrata Alloys to implement a work placed TB control program and provide pre-ART care  including TB screening and IPT to contractors. The Global Business Coalition is rolling out the TB/HIV tool kit developed by Thibela staff to South African businesses. The GBC convened a Roundtable on “Increasing Corporate Engagement on Tuberculosis” in May 2009 to provide training on the TB/HIV tool kit, which was conducted by Aurum staff. Thibela TB staff has also used the tool kit in rolling out to other mines and businesses.

• Aurum has implemented a HIV and TB prevention program for employees of small and medium enterprises called the Emthonjeni project. TB screening and HIV testing and referral for HIV treatment and care are offered at taxi ranks, through which SME employees pass on a daily basis and to surrounding SMEs. Since October 2008, 2,713 individuals at the Bree Street Taxi rank and 5,661 individuals at SMEs have been screened for TB.
• Aurum is implementing a project to reduce the risk of TB in the households of platinum miners with TB in the Rustenburg district modeled on the ZAMSTAR household intervention. Harmony Gold Mine has also requested assistance from Aurum to strengthen their TB control program.

• South Africa Advocacy Collaborations: CREATE-G provided scientific input into South Africa’s Treatment Action Campaign (TAC) literature on TB and HIV and initiated advocacy work to promote TB screening in antenatal clinics with the South African National Midwives Association.
• SA Satellite Symposia: Implementing the 3 I’s:  Thibela, ZAMSTAR and CREATE-G sponsored and implemented the symposium: Implementing the 3I’s prior to the SA National AIDS Conference in Durban in March 2009. Over 500 S.A. implementers participated in this high profile event.  Of note, the SA DOH was fully engaged in the meeting and publicly committed to promoting IPT implementation.  The proceedings are published in the July 2009 issue of the Southern Africa Journal of HIV Medicine.
• Infection Control Guidelines: Thibela has developed and is rolling out TB Infection Control Guidelines and Toolkit to businesses and the public sector.
• Kick Soccer 2010: The Desmond Tutu TB Center (ZAMSTAR/Western Cape) created a vibrant and powerful national TB Awareness campaign in tandem with upcoming SA FIFA World Cup 2010.  Using soccer balls as educational tools, animated character drawings depict the TB symptoms on each segment on the ball, together with the message:  if you have any of these symptoms, go to your nearest clinic.  The campaign is targeted to school children and will be accompanied by an educational session and video; children will be given the balls.  The National Department of Health and two other national departments in South Africa are partnering with the DTTC to make this a national campaign.   The campaign will be piloted in the 8 ZAMSTAR sites commencing in January 2010.   By working with national governments, DTTC has been able to promote the campaign without paying large FIFA sponsorship fees. Thibela serves on the national steering committee for the Kick TB.
• Campaign Training as Advocacy in THRio:  THRio PAC has identified community leaders in the favellas in Rio and has initiated an HIV/TB prevention program for impoverished areas. Over 1,000 person hours of training has been conducted among 68 community-based leaders in highly impacted HIV-TB burden areas to empower them to sustain TB/HIV advocacy in their favellas.  This innovative model will be featured in the CREATE annual meeting.
• Training for Sustainability in THRio Clinics: THRio PAC has trained clinic supervisors and other clinical staff in TB/HIV Integration Forums to promote sustainability of the IPT interventions.  This is another model which can be used to promote sustained delivery of IPT in Brazil and other countries.
• Promoting IPT through Change in Manufacturing of INH:   THRio is working with the national manufacturers of INH to produce Isoniazid in 300 mg tablet for ease of administration for prevention.
• Lancet Series: Health in South Africa:   One of the six papers published in the Lancet series on Health in South African focuses on TB/HIV and highlights the need to expand integration of TB/HIV services and IPT in particular. CREATE is acknowledged for support. The minister of Health and other government officials, academics, civil society and media will be attending the launch and symposium hosted by Aurum in August 2009.

 

Objective 3:  Transform global policies for controlling HIV-related TB through evidence-based advocacy.

• Research Fundamentals for Activists:  TAG and CREATE With TAG developed 70 page manual for TB advocates to advocate for increased research.  Approved by Advisory Committee after several iterations, in final edit before publication launch in October, 2009.
• How Research Can Help Control Tuberculosis:   Published in the International Journal of the Union against TB and Lung Disease, this June 2009 article by Dick Chaisson and Mark Harrington promotes the directions research needs to take to control TB.
• Promoting IPT to Low-Literacy HIV Clients:  CREATE-G has developed a cartoon series to educate low literacy HIV-infected persons to demand IPT.  After piloting in the Global Village at the Mexico City IAS conference, the final edition is available through the CREATE website and is now integrated into Thibela and ZAMSTAR advocacy work and remains the only cartoon-based advocacy for HIV patients.  
• CROI Symposium: The Stop TB TB/HIV Working Group and CREATE co-sponsored a TB/HIV research symposium at CROI (Montreal, Feb 2009), which raised the profile of TB among HIV researchers by sharing from ongoing studies; indentifying research needs and stimulating further collaboration.  Keynote addresses were given by Peter Godfrey-Fausett and Helen Ayles.
• IAS Symposium:  WHO, the TB/HIV Working Group of the Stop TB Partnership and CREATE, in collaboration with the International AIDS Society, Treatment Action Group and the Desmond Tutu HIV Centre, sponsored a highly visible meeting on HIV/TB research issues in conjunction with the 5th IAS Conference on HIV pathogenesis, treatment and prevention. The meeting will be held on July 18-19, 2009 in Cape Town, South Africa.  The meeting brought together notable researchers and leaders in the areas of TB prevention, childhood TB/HIV, TB treatment and diagnosis, and the interaction between HIV and drug resistant TB. Keynote speakers included Francoise Barre-Sinoussi, 2008 Nobel Laureate, Anthony S. Fauci, Director of the USA National Institute of Allergy and Infectious Diseases, and Mark Harrington, Executive Director of Treatment Action Group. The symposium served as a  platform for disseminating latest CREATE findings, including an update of IPT implementation to 30,000 miners from Thibela and ZAMSTAR community engagement activities and baseline prevalence data from ZAMSTAR.
• STOP TB Partners Forum: At the Partners Forum in Rio in March 2009, CREATE sponsored two symposiums bringing together community advocates and experts from multiple countries.   Engaging Community Health Workers and other Community partners in Finding and Treating TB highlighted a successful DOT program in an Eastern Kenyan prison, Thibela and CHW DOT in favellas in Brazil.  The symposium, Progress in Evaluating Current and New Tools to Improve TB Control, presented state-of-the-art advances in new tools research.   CREATE also brought the ZAMBART skills building workshop on Combating TB Stigma to the Forum where a multi-country group participated in the active interaction.

 

Objective 4:   Contribute to global advocacy efforts that aim to raise the profile of TB/HIV and address the $3 billion funding gap for TB/HIV in the Global Plan to Stop TB II.

Contribute to Global Advocacy efforts to raise the profile of TB/HIV.

• Engaging Communities in Research for HIV/TB:   CREATE has a wealth of on-the-ground experience in implementing community research and, in addition to peer-reviewed publishing, has a role in advocating for community-based research. To this end, CREATE-G conducted a Community Engagement in Research Meeting in Paris preceding the IUATLD Meeting.  Fifty international advocates attended and CREATE PAC Coordinators from all sites presented, as well as TAG, European ACTG and other NGOs.   The findings were subsequently published and distributed and are available on the CREATE Website.  A paper describing CREATE’s experiences in planning and conducting ethical large community-based trials has been written and will be submitted for peer-reviewed publication.
• Increasing Awareness of South African Miners and TB:   For World TB Day 2009, CREATE-G and AERAS co-sponsored a photography exhibit in Washington D.C.  The launch of this D.C. exhibit by internationally renowned photographer, David Rochkind, was used to raise awareness of the high TB morbidity and mortality among South African miners and the need for increased public health advocacy, funding and research.  Drs. Eldred and Sadoff (AERAS) spoke at the launch.
• Developing International Advocacy Leaders:  CREATE and TAG are continuing to collaborate on advocacy trainings targeting 14 Southern African countries. The latest training was conducted in Entebbe, Uganda.
•  Using the Media to Advocate for Increased TB/HIV Funding:  TAG and CREATE convened an International Press Conference at the IUATLD Meeting in Paris in October 2008. Participants included Nobel Prize Winner, Dr. Francois Barre-Sinoussi, Dr. Paul Nunn (WHO), Dr. Mel Spigelman (GATB), Dr. Richard Chaisson (CREATE) and Mark Harrington (TAG).   The need for sustained funding for TB and HIV was emphasized; this event was reported by Associated Press, L.A. Times, and 20 other international media outlets.

 

Address the $3 billion funding gap. 

• Obama Transition Team Advocacy:  CREATE-G participates in the Global Health Council TB Roundtable and worked with this core group to recommend increased funding to then President–elect Obama. The group subsequently met with an Obama transition team for TB and advocated for increased bilateral and multilateral TB funding and increased global PEPFAR accountability for TB/HIV integration. 
• Congressional Meetings and Briefings:  CREATE-G has taken advantage of its close proximity to Washington D.C. and has worked with Infectious Disease Society of America (IDSA) to educate D.C. lawmakers on the need for vigilance in the international fight against TB.  Drs. Eldred, Chaisson and Gounder have met with legislative analysts from Senators Cardin and Mikulski’s Offices, as well as Representatives Lowey and Cummings, to promote increased funding for the Global Fund and for bilateral international TB funding.  The appalling lack of basic knowledge about TB and its relationship to HIV reinforces the need for ongoing D.C.-based advocacy.  Though causality cannot be established, Rep. Lowey subsequently added $50 million for bilateral TB funding.   Also, Dr. Chaisson participated in the 2009 World TB Day Congressional Briefings to advocate for increase global TB/HIV funding.
•  Working with UNITAID to Promote TB Interventions:  UNITAID, a multinational funding agency for scaling up HIV, malaria and TB interventions in low income countries, has become an important player in supporting acquisition of diagnostics and drugs to control these diseases.  The leadership of UNITAID has solicited the collaboration of CREATE in setting their 2010 objectives, and Dr. Chaisson will participate in its first high-level consultation with implementing partner agencies in October.  The aim of the meeting is to establish a forum for countries in Eastern and Southern Africa and the islands of the Indian Ocean in which to share expertise and experiences to identify best practice and informing national and international strategic approaches.

 

Specific Activities of the WHO PAC Team

The WHO PAC activity has primarily focused on promoting the visibility of TB/HIV and accelerating the implementation of collaborative TB/HIV activities. The multifaceted global advocacy carried out by PAC has significantly contributed to the rapid increase in the rate of implementation globally.   Advocacy activities were enhanced during the reporting period both globally and nationally.  Advocacy efforts were aimed at key HIV stakeholders in an effort to catalyze implementation of the Three I’s, those activities that reduce the burden of TB in people living with HIV (Intensified TB case finding, provision of IPT and TB Infection control) as an essential part of HIV care.

Colleen Daniels, Technical Officer for TB-HIV Advocacy for STOP TB Department of WHO,  serves as the coordinator for PAC activities between CREATE-G and WHO; her position is partly funded under the WHO CREATE subcontract.  She has been instrumental in implementing CREATE/WHO programs.  Haileyesus Getahun is the key staff person involved in scientific activities with CREATE, and Paul Nunn oversees all activities and leads policy-related matters.

WHO has played a major, and often primary, role in the meetings listed above.  These meetings have successfully raised the profile of HIV/TB among HIV researchers, program managers, activists and other stakeholders by sharing data from ongoing studies, identifying research and policy gaps and stimulating further HIV/TB research. A skills building workshop held at the Partners Forum in Rio in March 2009 was particularly productive. Together with the Treatment Action Group, the workshop brought together civil society, former NTP managers and the Global Fund to discuss issues around resourcing TB/HIV, M&E, getting the most out of international forums, engagement in processes and getting your voice heard. The skills building session was well attended and participants found it very useful.

In an effort to catalyze implementation of those measures that reduce the burden of TB in people living with HIV, the Three I’s (Intensified TB case finding, Isoniazid preventive therapy and Infection control for TB) for HIV/TB campaign was initiated. A meeting of national TB and HIV program managers, from high burden English speaking countries from the Africa Region and representatives of technical and donor agencies was held in Addis Ababa, Ethiopia, in November 2008 to further consolidate nationwide implementation of collaborative TB/HIV activities particularly the Three I’s.  Three members of the CREATE Executive Committee participated in this meeting and presented evidence from the CREATE studies on the feasibility and impact of IPT and ICF for reducing the burden of TB.  A brochure on the Three Is calling for HIV stakeholders to think TB was developed and disseminated.  Fact sheets on TB/HIV global progress, IDU policy, infection control, IPT and roadmaps are prepared for each conference or meeting and disseminated throughout the conferences.

 

CREATE PAC Plans for the 2009-2011 

As the CREATE studies wind down,  PAC’s role shifts to planning for messaging around positive, negative and indeterminate study results and implementing a dissemination plan for study results.  The plan will include full use of the CREATE videos, which strongly visually present feasibility and roll-out of these large community-based TB/HIV programs.  The dissemination plan for the video, which includes country-specific and international targets, will serve as the template for the larger dissemination plan. CREATE will continue to work with Ogilvy to develop results messaging.  

CREATE’s policy and advocacy plans are evolving as the overall CREATE’s plan for delivery solidifies.   The PAC and the consortium are working towards integrating activities to maximize the impact of CREATE on delivery.  This may include training for delivery based on the broad guidelines CREATE is developing from its Standard Operating Procedures.

While looking to the future impact of CREATE, PAC will continue to implement activities relevant to the 4 overarching goals. The annual PAC meeting takes place October 10 in Cape Town, SA.  The planning committee for this event includes South African partners (ARASA, TAC, and TB/HIV Care Association), as well as all CREATE PAC partners.   As in previous years, the dual objectives are to increase advocacy skills of CREATE leaders and staff and to share the expertise of the regions advocacy network.  

PAC will continue to work collaboratively with its partners to maximize impact and effectiveness of advocacy work and increase the reach of activities.   PAC will train activists on research literacy and implementing the 3I’s and is working with ARASA and University of Cape Town to create a distance learning course for advocates that can be used globally.   CREATE-G is working with a number of partners to promote TB screening in antenatal clinics in Zambia and South Africa, as well developing plans with partners to control cross-border transmission of MDRTB and promoting improved TB diagnosis, prevention, and care for workers in mining and other industries. 

 

Plans for the Next Reporting Period

Year 6 of CREATE will be a year of tremendous activity.  The THRio study will complete its follow up phase in December 2009 and will have data collection continue through July 2010.  Analyses of the primary endpoints will begin toward the end of the Year.  The intervention has been fully adopted by the Rio de Janeiro Municipal Health Secretariat and will continue on after the project ends.  Staff from the study will be largely integrated into official roles in the Health Secretariat.  The ZAMSTAR study will be undertaking its final prevalence surveys beginning in October 2009 and will complete them late in Year 6.  Data analysis and follow up work will continue into Year 7.  Plans for integrating the interventions into the health services are under development in both Zambia and South Africa.  Thibela will finish the IPT intervention in its last cluster at the end of Year 5, with follow up continuing into Year 6.  Final prevalence surveys will be completed in seven of the clusters by the end of Year 6.

In addition to anticipated progress with the study processes, we expect that additional data on the safety and effectiveness of IPT will emerge from Thibela and THRio and that data on the yield of ECF and HH interventions will be forthcoming from ZAMSTAR.  Investigators from the studies will share results at international scientific meetings.  The Modeling project team will likely publish analyses using data from the DetecTB study.

 

Appendix 1 - Publications

 

Recent Core Publications:

Chaisson RE, Harrington M. How research can help control tuberculosis. Int J Tuberc Lung Dis. 2009;13:558-68.

Dowdy DW, Chaisson RE. The persistence of tuberculosis in the age of DOTS: reassessing the effect of case detection. Bull World Health Organ 2009;87:296–304.

Martinson NA, Moultrie H, van Niekerk R, Barry G, Coovadia A, Cotton M, Violari A, Gray GE, Chaisson RE, McIntyre JA, Meyers T. HAART and risk of tuberculosis in HIV-infected South African children: a multi-site retrospective cohort. Int J Tuberc Lung Dis. 2009;13:862-7.

Deluca A, Chaisson RE, Martinson NA. Intensified case finding for tuberculosis in prevention of mother-to-child transmission programs: a simple and potentially vital addition for maternal and child health. J Acquir Immune Defic Syndr. 2009;50:196-9.

Golub JE, Pronyk P, Mohapi L, Thsabangu N, Moshabela M, Struthers H, Gray GE, McIntyre JA, Chaisson RE, Martinson NA. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS. 2009;23(5):631-6.

Dowdy DW, Chaisson RE, Maartens G, Corbett EL, Dorman SE. Impact of enhanced tuberculosis diagnosis in South Africa: a mathematical model of expanded culture and drug

susceptibility testing. Proc Natl Acad Sci U S A. 2008;105:11293-8.

 

Recent Thibela Publications:

Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard GJ, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RPG, Lounis N, Meyvisch P, Verbeeck J, de Beule K, Andries K, McNeeley DF.  A Phase II Randomized, Placebo-Controlled Trial of TMC207, An Inhibitor of Mycobacterial ATP-synthase, in Multidrug-Resistant Pulmonary Tuberculosis. New Engl J Med 2009; 360:2397-405.

Charalambous S, Grant AD, Moloi V, Warren R, Day JH, van Helden P, Hayes RJ, Fielding KL, De Cock KM, Chaisson RE, Churchyard GJ. Contribution of reinfection to recurrent tuberculosis in South African gold miners. Int J Tuberc Lung Dis 2008;12:942-948.

Lawn S, Churchyard GJ. Epidemiology of HIV-associated TB. Current Opinion in HIV AIDS  2009; 4:325-33.

Girdler-Brown BV, White NW, Ehrlich RI, Churchyard GJ. The burden of silicosis, pulmonary tuberculosis and COPD among former Basotho goldminers. Am J Ind Med. 2008 51(9): 640-647.

Grant AD, Gothard P, Thwaites G. Managing drug-resistant tuberculosis. BMJ 2008;337:a1110.

Hanifa Y, Grant AD, Lewis J, Corbett EL, Fielding K, Churchyard G. Prevalence of latent tuberculosis infection amongst gold miners in South Africa. Int J Tuberc Lung Dis 2009;13:39-46.

Clark DA, Randera FM. Healthcare & Mining. African Analyst 2008; 3(1): 70-78

 

In Press:

Ben J Marais, Peter R Donald, Antony D Harries, Alfranio L Kritski, Rifat Atun, Saidi Egwaga, Paul Farmer, Wafaa El-Sadr, Mark Harrington, Gavin Churchyard, Mario Raviglione , Wange Londe, Alimuddin Zumla, Stefan Kauffman, Jamie Bayona, Christopher Whitty. Scale-up of services and research priorities for TB diagnosis, management and control - call to action. Lancet. (series on TB) 2010

Abdool Karim SS, Churchyard GJ, Abdool Karim Q, Lawn SD. HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response. Lancet. 2009.

Corbett EL, Zezai A, Cheung YB, Bandason T, Dauya E, Munyati SS, Butterworth AE, Rusikaniko S, Churchyard GJ, Mungofa S, Hayes RJ, Mason PR. Provider-initiated symptom screening for tuberculosis: diagnostic value, and the impact of HIV. Bulletin of the World Health Organization. 2009.

Lewis J, Charalambous S, Day JH, Fielding KL, Grant AD, Hayes RJ, Corbett EL. Churchyard GJ. HIV infection does not affect active case finding of tuberculosis in South African gold miners. Am Rev Respir Crit Care Med 2009

Cohen K, Grant AD, Dandara C, McIlleron H, Pemba L, Churchyard GJ, Smith P, Maartens G. The effect of rifampicin-based antitubercular treatment and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval concentrations in a South African HIV-infected population. Antiviral Therapy. 2009.

 

Guidelines:

GJ Churchyard, Mngadi KM. TB/HIV tool kit for South African businesses. Global Health Initiative. 2008.

Churchyard GJ. Co-author. Good Practice Guidance on HIV/AIDS, Tuberculosis and Malaria. ICMM. 2008.

Conference abstracts:

 

5^th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town

C.L. van Halsema, V. Chihota, K. Fielding, E. Russell, J. Lewis, F. Mota, G. Pilane, P. Molefe, G. Churchyard, A. Grant.  Good tuberculosis treatment outcomes and no evidence of increased drug resistance in individuals previously exposed to isoniazid preventive therapy in a population with high HIV prevalence. Abstract MOPEB021, Awarded IAS TB/HIV Research Prize

 

39th IUATLD Conference: October 2008, Paris, France 

Grant AD, Fielding K, Chihota V, Lewis J, Muller D, Luttig M, Popane F, Coetzee L, Churchyard GJ. Performance of TB screening prior to community-wide isoniazid preventive therapy among gold miners in South Africa. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008 [abstract PC-81882-19].

Fielding K, Chihota V, Lewis J, Luttig M, Crawford T, Popane F, Coetzee L, Muller D, Grant A, Churchyard G. Factors associated with prevalent TB at screening prior to isoniazid preventive therapy. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008 [abstract PS-81838-19].

Churchyard GJ, Coetzee L, Fielding K, Chihota V, Herselman P, Luttig M, Muller D, Popane F, Grant AD. Contribution of TB screening as part of community-wide IPT to TB case finding among South African gold miners. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008 [abstract PS-82143-20].

Churchyard GJ, Coetzee L, Popane F, Muller D, Luttig M, Ntshele S, Lewis J, Fielding K, Grant A. Feasibility of community-wide isoniazid preventive therapy among South African gold miners. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008. [abstract PC-82194-20]

Lewis J, Chihota V, Churchyard G, Grant A, Coetzee L, Crawford L, Luttig M, Muller D, Popane F, Fielding K. Factors associated with incident TB in the South African gold mines: a cohort study embedded within Thibela TB. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008. [abstract PS-82148-20].

Charalambous S, Morris C, Innes C, Shisana M, Churchyard G, Grant A, Rametsi L, Dowdeswell R, La Grange L, Fielding K. TB incidence in HIV-infected patients starting antiretroviral therapy in a South African mining population. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008. [abstract TS-82295-19] (oral presentation).

Harriet Park, Brendan V. Girdler-Brown, Rodney I. Ehrlich, Gavin J. Churchyard. Disease experience over one year of follow-up in a cohort of workers recently laid off from a South African gold mine: mortality, HIV and TB incidence, radiological change and lung function decline. 39th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Paris, France. 16-20 October 2008. [abstract PC-81682-18].

 

South African TB conference. July 2008, Durban, South Africa

Ndibongo B, Churchyard GJ, Fielding K, Chikhota V, van Zyl A. The cost effectiveness of MGIT versus LJ culture in the detection of smear negative TB. Oral presentation

Smanga Ntshele, Leonie Coestzee, Gavin Churchyard. Mobilising a community towards supporting a public health intervention

 

Recent THRio Publications:

 

Dowdy DW, Lourenço MC, Cavalcante SC, Saraceni V, King B, Golub JE, Bishai D, Durovni B, Chaisson RE, Dorman SE. Impact and cost-effectiveness of culture for diagnosis of tuberculosis in HIV-infected Brazilian adults. PLoS ONE. 2008;3(12):e4057. Epub 2008 Dec 29.

Golub JE, Durovni B, King BS, Cavalacante SC, Pacheco AG, Moulton LH, Moore RD, Chaisson RE, Saraceni V. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS. 2008 Nov 30;22(18):2527-33.

Pacheco AG, Saraceni V, Tuboi SH, Moulton LH, Chaisson RE, Cavalcante SC, Durovni B, Faulhaber JC, Golub JE, King B, Schechter M, Harrison LH. Validation of a hierarchical deterministic record-linkage algorithm using data from 2 different cohorts of human immunodeficiency virus-infected persons and mortality databases in Brazil. Am J Epidemiol. 2008 Dec 1;168(11):1326-32. Epub 2008 Oct 9.

Saraceni V, King BS, Cavalcante SC, Golub JE, Lauria LM, Moulton LH, Chaisson RE, Durovni B. Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2008;12:769-72.

 

Abstracts:

Saraceni V1, King B2, Pacheco AG3, Golub JE2, Cavalcante SC1, Moulton LH2, Moore RD2, Chaisson RE2, Durovni B1. Tuberculosis, HAART use and survival in the THRio Cohort, Rio de Brazil. XVII International AIDS Conference, Mexico City, 3-8 August 2008, Abstract MOAB0305.

Saraceni V, King BS, Cavalcante SC, Golub JE, Arduini D, Chaisson RC, Durovni B. Ruling out tuberculosis to start preventive therapy in HIV co-infected patients as an opportunity to find TB 39th Union World Conference on Lung Health, 16-20 October 2008, Paris, France: PC-81859-18.

 

Recent ZAMSTAR Publications:

Ayles H, Schaap A, Nota A, Sismanidis C, Tembwe R, De Haas P, Muyoyeta M, Beyers N; Peter Godfrey-Faussett for the ZAMSTAR Study Team. Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications for tuberculosis control in the era of HIV. PLoS ONE. 2009;4(5):e5602. Epub 2009 May 19.

Ayles HM, Sismanidis C, Beyers N, Hayes RJ, Godfrey-Faussett P. ZAMSTAR, The Zambia South Africa TB and HIV Reduction study: Design of a 2 x 2 factorial community randomized trial. Trials. 2008 Nov 7;9:63.

Mueller DH, Mwenge L, Muyoyeta M, Muvwimi MW, Tembwe R, McNerney R, Godfrey-Faussett P, Ayles HM. Costs and cost-effectiveness of tuberculosis cultures using solid and liquid media in a developing country. Int J Tuberc Lung Dis. 2008 Oct;12(10):1196-202.

Murray EJ, Marais BJ, Mans G, Beyers N, Ayles H, Godfrey-Faussett P, Wallman S, Bond V. A multidisciplinary method to map potential tuberculosis transmission 'hot spots' in high-burden communities. Int J Tuberc Lung Dis. 2009 Jun;13(6):767-74.

Muyoyeta M, Schaap JA, De Haas P, Mwanza W, Muvwimi MW, Godfrey-Faussett P, Ayles H. Comparison of four culture systems for Mycobacterium tuberculosis in the Zambian National Reference Laboratory. Int J Tuberc Lung Dis. 2009 Apr;13(4):460-5.

Sismanidis C, Moulton LH, Ayles H, Fielding K, Schaap A, Beyers N, Bond G, Godfrey-Faussett P, Hayes R. Restricted randomization of ZAMSTAR: a 2 x 2 factorial cluster randomized trial. Clin Trials. 2008;5(4):316-27