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 6, from 1 November 2009 through 31 October 2010.  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. 

 

GENERAL PROGRESS

CREATE has had a highly productive year, achieving substantial progress in reaching study milestones, making major contributions to global policy and national guidelines, accelerating work on modeling interventions using study and other data, and initiating and continuing partnerships with implementers, normative bodies and funders to promote deliverability of TB/HIV interventions. 

With respect to the three CREATE cluster-randomized trials, progress has been steady and on-target in the final stages of these diverse studies.  The THRio study in Rio de Janeiro has completed its intervention phase and is in the final stages of data collection and cleaning.  Results of the study will undergo preliminary analysis in September 2010 and will be presented at the CREATE Annual Meeting in Cape Town, in November.  Final prevalence surveys for the ZAMSTAR study were launched this year and are expected to be completed by December 2010.  Follow up in the last intervention cluster for the Thibela TB study was completed in July 2010 and final prevalence surveys are under way, to be completed in approximately one year.  Thus, all three studies have been successfully executed and results are either forthcoming or nearing completion. 

In Policy and Advocacy, CREATE investigators and data played a prominent role in the development of new World Health Organization policies and clinical practice guidelines for isoniazid preventive therapy and intensified TB case finding in HIV-infected individuals, prepared during a January 2010 consultation in Geneva and recently promulgated.  These guidelines adopt the principal interventions used in the CREATE studies and should have a marked effect on clinical practice in high burden areas.  Additionally, detailed results of experience with isoniazid preventive therapy in the CREATE studies have been compiled into a special supplemental issue of the journal AIDS which will be published in November 2010 and should promote wider uptake of this intervention. 

Modeling of interventions has been particularly powerful in promoting earlier use of antiretrovirals in the past year, and the CREATE modeling project is maturing in its efforts to bring similar analyses to bear on TB/HIV interventions. 

Activities to promote the deliverability of CREATE interventions have yielded tangible and promising results in the past year.  In Ethiopia, work with PEPFAR partners has resulted in the establishment of remote laboratories to support intensified TB case finding in both clinical and community settings, and roll out of isoniazid preventive therapy is likely to begin in the coming year.  Collaboration with the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) in Lesotho, Swaziland, Tanzania and Cote D’Ivoire is leading to integration of TB/HIV interventions in PMTCT programs and ART clinics.  Strategic investment by CREATE and EGPAF in Lesotho will help launch an important demonstration project for intensive case finding and isoniazid preventive therapy in antenatal clinics in one of the highest burden areas for co-infection in the world. In Malawi, a collaboration between the CREATE Administrative and Modeling Cores, the Ministry of Health and Medecins sans Frontieres has received an outstanding score on an NIH grant application to implement and evaluate molecular diagnostics (GeneXpert) as part of intensified case finding and screening for isoniazid preventive therapy in ART clinics.  If funded, this project will serve as a national demonstration project for both molecular TB diagnostics and integration of TB/HIV interventions in a very resource-limited setting with a high burden of disease.

Finally, deliverability activities at the national level in Brazil, South Africa and Zambia are moving forward rapidly.  In South Africa, new national guidelines for isoniazid preventive therapy were orchestrated by the Thibela TB and CREATE PAC teams and are among the most progressive and far-reaching in the world.  In Brazil, based on data from the THRio study, integration of isoniazid preventive therapy with ART has been expanded nationally and is now the responsibility of the National HIV/AIDS Program.  In Zambia, the ZAMSTAR study is conducting demonstration projects for isoniazid preventive therapy for the Ministry of Health and has established containerized TB diagnostic laboratories that will be turned over to the government following completion of the study’s prevalence surveys, essentially quadrupling the laboratory capacity for TB diagnosis in the country.

Overall, the CREATE project is making great strides in achieving its overall strategy to transform global policies and practices for controlling HIV-related TB through the use of evidence and advocacy.

Specific Results

Describe the planned milestones, outputs, or outcomes1 for the reporting period and whether they were achieved or delayed	If achieved: What source of evidence2 do you have to support the result? If delayed: What was the cause of delay?
Objective 1:
To develop, evaluate, and promote new public health strategies to reduce the incidence of tuberculosis in settings of high HIV prevalence.	Milestones largely met. The cluster-randomized trials evaluating novel public health strategies are well underway and on target to finish according to previously modified and approved timelines.  THRio has completed its intervention and analysis will begin in September.  ZAMSTAR and Thibela TB are conducting final incidence and prevalence surveys.   ZAMSTAR will finish its prevalence surveys in December and analysis will commence in early 2011.  Thibela TB will be completed in June 2011, with analysis commencing in July.  Data from the studies are already available and are influencing policy and practice globally.  The evidence of this progress is contained in publications describing the design and preliminary results from the studies, in the report from the CREATE DSMB, and in site monitoring reports by the CREATE Administrative Core.
Objective 2:
To transform global policies for HIV-related TB through evidence-based advocacy.	CREATE has had a substantial impact on global TB/HIV policies since its inception.  Evidence of this is contained in the WHO Interim Policy on Collaborative TB/HIV Activities, published shortly after CREATE developed its scientific agenda (http://whqlibdoc.who.int/hq/2004/WHO_HTM_TB_2004.330_eng.pdf). Additional evidence of CREATE’s influence in policy development is the WHO recommendations for diagnosing and treating smear-negative pulmonary and extrapulmonary TB in resource constrained settings (http://whqlibdoc.who.int/hq/2007/WHO_HTM_TB_2007.379_eng.pdf).  A large quantity of the data used to formulate these policies were generated by CREATE and FIND collaborative projects.  Further evidence of impact is contained in the WHO Three I’s Policy, based on two of CREATE’s primary strategies, isoniazid preventive therapy and intensified case finding (http://www.who.int/hiv/pub/meetingreports/WHO_3Is_meeting_report.pdf). Major progress with ICF and IPT policy was achieved with development of new evidence-based guidelines in January 2010 at a meeting in which six CREATE senior investigators participated.  These guidelines will be published shortly.  WHO guidelines for intensified case finding and isoniazid preventive therapy for tuberculosis for people living with HIV in resource constrained settings, Geneva, WHO, 2010. New guidelines for isoniazid preventive therapy and intensified TB case finding were issued in South Africa in March 2010.  Thibela TB organized the meeting and CREATE study and PAC members participated.

 

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, the CREATE projects are well along in achieving their aims.  The table below summarizes the primary aims of each study, the population receiving the interventions and the status of each with respect to measuring its primary endpoints. 

	Thibela	THRio	ZAMSTAR
Primary aims	To determine the effectiveness of widespread use of IPT in South African gold mining communities for reducing the incidence of TB.	To determine the impact on TB incidence of widespread use of TB screening and IPT in HIV-infected patients with access to ART in Brazil and to determine the relative impact of IPT and ART on TB incidence.	To determine the effectiveness of community-based TB diagnosis and household TB and HIV interventions for contacts of new TB cases for reducing community prevalence of TB.
Population	Gold mining communities, including all surface and underground workers, at 15 South African gold mines.	HIV-infected adults receiving HIV care, including ART, in 29 public clinics in Rio de Janeiro.	Residents of 24 communities in Zambia and South Africa (total population >1.2 million). Sample size for prevalence surveys now 4,000 per cluster; power is unchanged.
Status for ascertaining primary endpoints	TB incidence following intervention or control has been ascertained in 13 of 15 clusters. The remaining two clusters will finish ascertainment by December 2010.	Final data collection will be completed by August 31, 2010.  Analysis was begun in September 2010.	Prevalence surveys began in October 2009 and will finish in December 2010.  Analysis will commence in 2011.

 

INDIVIDUAL STUDY PROGRESS REPORTS

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 TSTs and IPT has significantly increased in clinics post-intervention and that patients received the interventions more quickly (Figures 1 & 2).

Study outcomes have been 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 reviewing patient charts for study outcomes using data abstraction forms which include: 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 the study follow-up period and each clinic has had at least four abstraction visits and all collected data has been entered into the study database.  Data collection was completed in June 2010 and additional data cleaning and supplementation is ongoing through August 2010.

Kaplan-Meier plots have been generated for process data from the study to describe time to TST and time to IPT for TST-positive individuals (Figures 1 & 2).  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. 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 1.  Time from first clinic visit to TST reading in TST-eligible patients in the THRio clinics, before and after intervention. 

 

 Figure 2.  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 2.1 cases per 100 person years.  Approximately 42% of all new TB cases diagnosed during the THRio study have been diagnosed at entry into the clinic, thus emphasizing the strong need for earlier HIV-diagnosis. As a result the effectiveness of IPT, the THRio intervention, is greatly compromised as we are unable to target a large proportion of patients –19% of all patients – have either a history of TB diagnosis or were diagnosed with TB upon entry.  As expected and seen elsewhere, TB incidence is markedly lower in individuals receiving HAART compared to HAART naïve patients (1.8 vs. 3.6 cases per 100 person-years).  Both our baseline and update analyses confirm the effectiveness of IPT for preventing TB, especially in TST+ individuals.  As shown in the figure below, TST+ patients who receive IPT have an enormous reduction in TB incidence.  Consistent with recent data from the CDC’s BOTUSA study in Botswana, TST- individuals receive little benefit from IPT.  Of note, however, is that TST unknown patients, who account for 58% of all TB cases in THRio, appear to benefit from IPT, though to a smaller extent than TST+ patients.  This suggests that a policy of offering IPT to all patients until they are known to be TST- may be an appropriate strategy to reduce TB incidence in Rio de Janeiro.

 

Figure 3. Kaplan-Meier estimates of TB incidence by TST status in THRio.

 

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.  Table 1 shows the distribution of types of diagnoses for the 805 TB cases for which data collection is complete.  Please note that this includes both pulmonary and extrapulmonary TB cases.  This information was shared with the DSMB in June 2010.

 

Table 1.  TB case definition (N=815) in the THRio study.

 

Based on our analyses and discussions with the DSMB, we now plan to re-evaluate clinical and electronic database records from patients who do not meet the case definition to determine if more information on clinical response can be identified, so these patients can be more accurately classified for analysis.

 

Thibela TB

Thibela TB has completed the intervention phases of the study with 27,861 individuals having consented to the study, and 24,152 mineworkers being started on isoniazid preventive therapy (IPT). In the latter clusters entering the study a consent rate of over 80% of the targeted populations was attained. This is a remarkable achievement in a study of this magnitude. Furthermore, the main study database was cleaned and locked down a mere month after the intervention ended – this is a new standard in data management for large public health cluster randomized trials. Thibela TB continues to inform policy and practice of IPT internationally and nationally.

The project’s progress against objectives is on track as per the plan submitted to CREATE in 2008. Financially the study is within acceptable budget variation parameters for Year 6 and within grant limits for the project overall. Progress, challenges, preliminary results, ancillary studies and outputs are described.

Progress with respect to the various study activities and timeline is described below and summarized in the activities table.

 

The main intervention: Final recruitment, retention and adherence data

All eight intervention clusters have completed enrolment. In total, 27,861 individuals consented to the study. The sum of the mid-point intervention cluster sizes from Human Resources data was 41,697 employees and contractors, giving an uptake to the study of 66.8%. Of these 27,861 participants, 24,630 (88.4%) were eligible for IPT and so 24,152 of 41,697 employees and contractors started IPT, representing 57.9% of the workforce in intervention clusters. Figure 1 shows the percentage uptake by cluster, using mid-point workforce size as the denominator, showing substantially higher uptake in later clusters (note that there is staggered enrolment of clusters and so the month of recruitment does not represent the same calendar period for each cluster).

 

 

Figure 4: Cumulative percentages that have consented to the intervention, by month of recruitment and cluster.

 

Retention is an issue for all IPT studies, but through considerable efforts using education, incentives and active follow-up of participants, reasonable retention has been achieved in Thibela. Of the participants who have sufficient follow-up time, more than half have been dispensed the 180 days of INH that is considered to be an effective dose (13,154/24,104 = 54.6%). There are substantial cluster level differences in this measure of retention (35.2% - 78.5%). For the later four clusters the mean % is 65% compared with 48% for the earlier four clusters. Self-reported adherence was very good with 90.6% of participants who returned on time reporting that they had not missed any tablets in the last three days. There was some cluster level variation in this (84.4% - 93.8%).  Retention by cluster is shown in Figure 5 below.

 

Safety profile

There were 132 study defined adverse events reported, regardless of subsequent stopping of INH, representing 0.5% of the 24,152 participants who ever started INH.  Only 8 of these were severe or life-threatening, and one death occurred which was attributed to INH. Overall, the level of adverse events has been favorable and consistent with published experience.

 

Final Prevalence Survey study

As of May 2010 the final prevalence survey had started in 8 clusters, with a total of 6606 participants being recruited. By the end of 2010 a further 6 clusters will have begun enrolment and with the last cluster initiating the survey in February 2011.

 

Figure 5.  Retention on IPT by cluster for Thibela TB.

 

 

TB Case Ascertainment (TCAS) study

In December 2010 the TCAS study changed to data abstraction of a reduced number of data sources (TB record card and laboratory data) and will continue to collect data on TB episodes to February 2011.

ZAMSTAR

Accomplishments

Year 6 has been an important year of transition for ZAMSTAR.  The intervention period is complete and the measurement of the primary and secondary outcomes is now the overriding priority.  While awaiting the results of the trial, the deliverability team is engaging with other providers to maximize the continuity of the interventions in the intervention areas, to scale-up intervention in other non-ZAMSTAR sites and to prepare for interventions more widely, including the non-intervention sites.

ZAMSTAR has remained closely involved with national, provincial, district and local health services in both countries as well as with the international policy-setting arena and this has led to a range of opportunities to help shape policy and activity around tuberculosis and HIV, but not necessarily directly related to the ZAMSTAR study.

 

Primary outcome surveys

The primary outcome is the prevalence of culture positive tuberculosis, measured in a random population sample in each of the 24 ZAMSTAR communities.  This is a huge undertaking requiring detailed planning, training, management and quality assurance for the fieldwork, laboratory work and data management.  More than 100 staff in each country have been trained in the standard procedures for the survey.  Several lessons were learned from the experiences of the baseline surveys, which were conducted in 4 similar communities, that were not part of the ZAMSTAR study itself.  As a result, ZAMSTAR has moved to collect data using PDAs in the field, which has proved to be a very positive change despite the initial cost and the extensive training required.  Data are collected, backed up and transferred to Lusaka and Cape Town data centers, almost in real time allowing the team to know that more than 30,000 adults have been interviewed and given sputum samples to date.  The survey also encourages the selected adults to undergo HIV testing, either within their household, or at a dedicated counseling and testing facility within the community.  In many communities, 80-90% of the entire adult population sampled, is choosing to learn their HIV status.  In other communities the rate is lower, but data on acceptability of door to door counseling services will be important in designing future community-based HIV interventions.  The surveys are also capturing data on a range of chronic non-communicable causes of ill health including diabetes, smoking and obesity, and in South Africa, the Department of Health has asked ZAMSTAR to include hypertension in the survey to complete the picture with regard to the major cardiovascular risk factors.  The baseline surveys demonstrated that the laboratory capacity was inadequate, so ZAMSTAR in Cape Town refurbished and extended their culture facilities, while in Zambia the first decentralized tuberculosis culture facilities have been established in purpose-designed containerized laboratories to allow the processing of so many samples.  More than 30 staff have been trained in both countries in mycobacterial culture, and Ministry of Health personnel have had their training refreshed.  The “minilabs” will remain part of the Zambian Government’s effort to scale-up culture facilities and to provide drug susceptibility testing for the first time outside Lusaka.  The labs and the ZAMSTAR experience and protocol are also being used for the planning of a National Prevalence survey in Zambia.  These containerized “minilabs” have also proved of great interest to many others and the ZAMSTAR team is now advising on the design, installation and supervision of similar systems for other countries in the region in collaboration with FIND and PEPFAR.

 

Secondary outcomes

Secondary outcomes are measured at both the community and the household level.  At the community level ZAMSTAR has completed the follow-up TST surveys that will be used to estimate rates of tuberculosis transmission in the community.  Children enrolled in grades 1-3 at the start of the study have been followed in all 24 communities, either through the school system, or by linking them to their homes.  A number of children have, of course moved away, died or been lost.  During the follow up TST cohort 4903 tests were read in South Africa and 8313 in Zambia.  Losses to follow-up are similar to those anticipated in the protocol and slightly better than predicted in last year’s annual report.  Any biases that can be demonstrated between those retested and those who moved away from the sites, refused consent or were lost are being explored.  Around 30% of the cohort were missing, moved or lost.  Of those still present after 3 years, over 85% gave consent and over 98% of these had a skin test placed and 98% were available for skin test reading.

The routine tuberculosis data has been captured electronically which allows the other community level secondary outcomes to be measured, and also supports the district tuberculosis programs to enhance and improve their monitoring and evaluation.  Unfortunately, the data do demonstrate the challenges that many districts have in providing reliable tuberculosis notification and cohort analysis data to the national tuberculosis programs in both countries.  ZAMSTAR has been working to improve the data quality.

At the household level, the second visit to the secondary outcome cohorts was completed last year and the third round is about to start.  The social science team has developed a framework for describing and measuring different aspects of stigma that remain major impediments to control of both HIV and tuberculosis.  The analysis of whether the interventions have had an impact on stigma in the household is being planned.

The secondary outcome cohorts also provide a platform for the additional longitudinal studies that are being done as doctoral projects by two of the ZAMSTAR doctors, one studying whether interferon-gamma release assays are better than the tuberculin skin test at predicting which people will develop tuberculosis and one studying whether the household intervention leads to better control of HIV infection through increased detection, earlier treatment and better adherence.

 

Dissemination, Communication and Engagement

Accomplishments are laid out in the PAC report.  Year 6 has seen much greater local involvement in Zambia with excellent relationships developing with the media through training and closer engagement.  The DTTC website has also been updated.  In both countries, ZAMSTAR has been working with the communities to manage the sensitive transition from intervention to outcome measurement.  Dissemination meetings have been held in each of the community sites feeding back lessons from the interventions and sensitizing communities and the staff in the district and clinics about the outcome surveys.  Deliverability is discussed below.

ZAMSTAR remains a key partner for national and provincial tuberculosis control programs, and is consulted on many policy and strategy decisions.

Many advocacy activities were held of which the biggest is the “Kick TB 2010” campaign in collaboration with the South African National Department of Health and the National Department of Education. 

 

Research infrastructure

ZAMSTAR has built an impressive infrastructure for research on interventions based in the community.  In all 24 sites, we have excellent working relationships with the district health services, with the community leaders and opinion makers and with the population in general.  These sites are electronically mapped, linked by virtual networks to databases in Lusaka and Cape Town and staffed by energetic, engaged research assistants, most of whom come from the communities and have now been trained in good clinical practices, research ethics, data collection and specific skills for each component of ZAMSTAR.  This infrastructure has already led to a number of possibilities for future research laid out in the deliverability section.

 

Modeling Project

The implementation of the Modeling Project was delayed for approximately one year, as reported in the 2009 Annual Report.  As a result, Year 6 of CREATE was Year 2 of this project, rather than Year 3.

 

Major activities and milestones

1.     Progress

During Year 2, the development of prototype models for case-finding studies and their application using DETECTB and national Zimbabwean HIV and TB data, have met Objective 1a, Major Activity 1 and 2. Initial progress has also been made in fitting these models for case-finding studies to ZAMSTAR data, initiating activity on Objective 1a, Major Activity 3.

The collation of the Bethel data and the fit of the deterministic model to these data were used to make preliminary estimates of the long term protection from re-infection following TLTBI, meeting Objective 1b, Major Activity 1. The initial exploratory deterministic model development and its application to Thibela baseline data was used to identify factors affecting the impact of community-wide IPT (meeting Objective 1b, Major Activity 2).

A methodology was developed for interpreting tuberculin skin tests in populations with a high prevalence of HIV, Tuberculosis, and nonspecific tuberculin sensitivity (Objective 2, Major activity 1), using available TST and IGRA data from Zimbabwe. This methodology has been published and can be applied to ZAMSTAR SOCS data once these data are available for modeling use. 

The protocol and ethics forms for the fieldwork to collect contact data in the ZAMSTAR communities have been drafted, starting activity on Objective 2, Major activity 2. This activity will be completed in Year 3.

 

2.     Changes

Dr Richard White (Senior Lecturer in Infectious Disease Modeling, LSHTM) and Prof Richard Hayes (LSHTM) have taken over from Dr Liz Corbett as PI of this project (from Sept 2010). This decision, due to the relocation of Dr. Liz Corbett from Zimbabwe to Malawi, has been endorsed by all parties, including Dr. Moulton, PI of the Biostats Core and Prof Dick Chaisson.  Dr. Corbett will remain a key investigator on the project. 

We anticipate that this reorganization will enhance the productivity of the project and will greatly facilitate the transfer and use of data from the Thibela and ZAMSTAR studies, as the biostatisticians working on these trials are also fully integrated into the Biostats Core.  Thus, several steps in the process of accessing data will be eliminated.

As originally planned, Dr. Peter Dodd, who has been working on Objective 1a and will continue to work on this objective and Objective 2, major activity 2 and Objective 3, has moved from Imperial College to LSHTM (from July 2010).

 

3.     Challenges

The main anticipated challenge was the difficulty of modeling TB in gold miners, given the number of different exposures that place them at high risk of TB (HIV and silicosis, and congregate living).  In this context it is disappointing to have found relativity little to guide us from the Alaskan data, other than the high rate of reactivation disease consistent with the high prevalence of radiological, but untreated, tuberculous scarring in this population. However, we still anticipate that it should be possible to provide estimates and projections for the intervention and that sufficient data exist to allow estimation of a number of key outcomes, including:

• The likely relative contribution of the following factors to differences in the observed impact of IPT between clusters:

1. Population characteristics (age distribution and proportion of miners at different stages of silicosis);
2. Characteristics of the implementation of IPT (the rate at miners were recruited into the intervention, adherence to IPT).

• To predict the time until the incidence would be expected to rise after cessation of IPT and whether providing further IPT e.g. 1-5 years after the end of the current intervention would improve the impact.
• To identify what the optimal coverage of IPT would have been in each cluster to attain the maximum reduction in incidence and for the reduced incidence to be maintained as long as possible.

 

4.     Unexpected results

The main unexpected outcome from the exploratory modeling that preceded the case-finding model, was that as HIV epidemic goes into decline, the relative rate of TB by HIV status is expected to peak (as is being observed throughout Africa) and then go into decline, due to a falling prevalence of latent TB infection with time-since-HIV infection that partly compensates for the increasing risk of reactivation due to more advanced immunosuppression.  This reflects the intrinsically unstable nature of latent TB infection in the HIV-infected host.  This finding does not take the unusually high exposure to M. tuberculosis that occurs in health facilities into account, although this can be considered in the newly developed micro simulation model (Objective 1a).

The main unexpected finding from the modeling of community-wide preventive therapy (Objective 1b, Major activity 2), was the high risk of reactivation (0.8% per year) that may reflect the extremely high prevalence of untreated but radiologically apparent (healed) TB in this population, which was ~ 50% at the start of the intervention.

 

5.     Expected outcomes in years 3 and 4

The field work to collect data in the ZAMSTAR communities (Objective 2, Major activity 2) will lead to a high quality description of differences in contact patterns between ZAMSTAR communities and may provide part of the explanation for the heterogeneity in TB incidence between the ZAMSTAR communities. These data will also be used to parameterization the spatial kernel that will be used in the micro simulation model used in later objectives.

The ZAMSTAR (ECF/HH) intervention model impact fits and projections (Objective 3, Major activity 2) will lead to an improved understanding of the ZAMSTAR (ECF/HH) empirical trial impact and enable longer term projections of impact to be made.

The deterministic IPT modeling of the contributions of different factors to observed Thibela (IPT) impact (Objective 3, Major activity 3) should lead to improved understanding of Thibela (IPT) trial impact, and the model projections to meet Objective 3,Major activity 4 should lead to an improved understanding of the durability of the IPT intervention, the impact of providing further IPT, estimates of the optimal coverage of IPT, and enable generalization of these results to other populations.

If time permits, finalizing the IPT component of the micro simulation ECF model and the handover to CREATE core funding for combined intervention projections (Objective 3, Major activity 5), should lead to an improved understanding of likely impact of combined ECF + IPT interventions and other hypothetical combination interventions in South Africa and Zambia and other populations.

Project results will be disseminated by manuscript publication, scientific meetings and policy briefing.

A summary of the project objectives, key activities, expected outcomes and progress is shown in Table 2. In line with the changes to the project years in CREATE, Year 1 refers to Sep 07-Oct 09, Year 2 is Nov 09- Oct 10, Year 3 is Nov 10- Oct 11 and Year 4 refers to Nov 11-Oct 12.

Table 2 Summary of modelling project objectives, key activities, expected outcomes and progress

Objective	Major Activity	Expected overall outcome	Progress
Study governance and communication	1 Formation of Steering Committee	Effective communications & guidance	Complete
	2 Intervention and modeling workshops	Workshops held to discuss progress, identify problem areas and future direction. Scientific and policy dissemination	Annual
1a: Development of prototype model for case-finding studies	1 Micro simulation model development	Develop principles & explore properties of simple models	Complete
	2 Micro simulation model fitted to DETECTB data	Model developed, fitted to data & paper published	Complete
	3 Micro simulation model fitted to ZAMSTAR data	Model fitted satisfactorily to data & paper published	Year 2/3
1b: Development of prototype deterministic model for community-wide IPT	1 Collect & fit model to Bethel data to make preliminary estimate long term protection from re-infection following TLTBI	Data collected. Preliminary estimate of long term protection from re-infection following TLTBI. Paper published	Year 2/3
	2 Initial exploratory deterministic model development and applied to Thibela baseline data to model factors affecting the impact of community-wide IPT	Model developed. Factors affecting Thibela trial impact identified.	Complete
	3 Model fitted to Thibela trial b'line and notification data	Model fitted to data	Year 3
2: Identify and, through field work, define key parameters and assumptions to which modeling is highly sensitive	1 Analyze TST/IGRA data	Data analyzed and paper published	Complete
	2 Conduct field work	Complete field work. Better understanding of heterogeneity in TB incidence and contact pattern differences between ZAMSTAR communities. Paper published	Year 3
3: Final model development, validation and fitting, projection	1 Fit models to trial outcome data	Model with good fit to trial outcome data	Year 4
	2 ZAMSTAR (ECF/HH) intervention model impact fits and projections	Improved understanding of ZAMSTAR (ECF/HH) trial impact and longer term projections. Paper published.	Year 4
	3 Determine contributions of different factors to observed Thibela (IPT) impact	Improved understanding of Thibela (IPT) trial impact. Paper published.	Year 4
	4 Projections of the durability of the intervention / impact of providing further IPT / optimal coverage of IPT / generalisability	Improved understanding of Thibela trial durability / impact of providing further IPT / optimal coverage of IPT / generalisability. Paper published.	Year 4
	5 Finalize IPT component of microsimulation ECF model & handover to CREATE core funding for combined intervention projections	Micro simulation model with ECF+IPT component. Well defined and well-fitting models. Improved understanding of ECF + IPT impact. Paper published.	Year 4

 

Changes

Administration Core: Virginia Kline left Hopkins in August 2010.  Mita Sahu was hired to replace her as administrative coordinator.

Biostatistics Core: None noted.

Education and Training Core: None noted.

Policy and Advocacy Core:  None noted.

 

THRio:

5 field supervisors finished their work in December 2009 as the intervention process ended.

 

Thibela TB:

Staffing

The study director (Dr Leonie Coetzee) and the Regional Manager for the Welcome region (Ms Flora Popane) have left the study to pursue career opportunities elsewhere. We elected not to fill either position. Prof Churchyard has taken over the responsibilities of the study director and Senior Team Leader for Welkom has taken over the responsibilities of the regional manager. The weekly Thibela operations meeting is chaired by one of the Principal Investigators.

 

Laboratory procedures

For logistic and economic reasons a decision was made to centralise all laboratory procedures being done by the National Health Laboratory Service and Barc laboratories to the National TB Reference Laboratory in Sandringham, Johannesburg, under Dr Gerrit Coetzee. 

Funding became available through Dr Susan Dorman’s R01 grant to determine the performance characteristics of the Cepheid Xpert MTB/RIF system in a prevalence survey, which started in May 2010.

 

TB case ascertainment study

With all clusters contributing to the TB case ascertainment study (TCAS) the human resource requirements to conduct TCAS exceeded existing capacity. In order to manage within existing human resource capacity ethics approval was obtained to do case note extraction of data from TB record cards, registers, existing TB and laboratory without specific informed consent from every individual (TCAS-lite).

 

ZAMSTAR:

The transition to outcome measurement led to some changes in staffing and management responsibilities, with new team leaders being appointed and management delegated to Elizabeth du Toit in South Africa and Monde Muyoyeta in Zambia.  The prevalence surveys started several months later than anticipated to allow for logistics, management and training to be strengthened.  This means that the budget for year 5 was underspent, as some of the refurbishement, equipement and laboratory supplies were procured in year 6.  The underspent balance will be absorbed in year 6 and we will overspend in year 7 to allow the prevalence survey to be completed.  The funds carried forward from previous years due to currency gains, interest payments and efficiencies allow us to be confident that ZAMSTAR will deliver the primary outcome within its projected total budget for the project. 

Babis Sismanadis left the biostatistics core to join WHO and has been replaced by Justin Fenty, who has extensive experience of data handling and analysis from large African field based projects.  He is rapidly learning the complexities of the ZAMSTAR databases and will be able to streamline the data management process in anticipation of the main analyses.  He has already made important contributions to the analysis plan and to this year’s DSMB report

The PAC Units in both countries have also changed.  Justin O’Brien now leads a strengthened Zambian team.  Amanda Kruger has left the South African team and her responsibilities will be shared between Wena Moelich and consultants as necessary.

 

Modeling Project:

See above.

 

Challenges

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

 

THRio: The primary challenge facing THRio is continued assurance of proper implementation of the intervention and ongoing training and re-training of current and new clinic staff now that the intervention has ended.  New clinic staff are 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 achieve 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 strong step towards TB/HIV program 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: Main Database close out: The intervention in Thibela TB consists of screening for tuberculosis and eligibility for IPT, followed by nine monthly visits for further dispensing and follow-up for safety and tuberculosis. All of these data were captured into the Main Database prospectively for close to 30,000 participants. A deadline was set to have all data cleaned and locked within one week of the last participant completing the intervention. This required considerable work and co-ordination by the regional study teams, data management and the study statisticians; this deadline was successfully achieved.

Final Culture Prevalence Survey: As mentioned in the previous annual report, the initial method of recruitment to the Final Culture Prevalence Survey proved inadequate, with very low uptake. As a result, the recruitment strategy was changed to take place during the annual occupational health screen that all miners must undergo. This new strategy has been very successful, with vastly improved uptake and the Final Culture Prevalence Survey is now back on schedule.

Changing laboratory: We have changed the laboratory used for the Final Culture Prevalence Survey, from a private laboratory (BARC) to the new TB Reference Laboratory at the National Health Laboratory Services. This has required substantial work to ensure standardization of all procedures with the previous laboratory and following a successful pilot, the laboratory switch has been finished. This new strategic partnership has allowed us to include an evaluation of the GeneXpert system versus MGIT culture in the Final Culture Prevalence Survey.

Termination of contracts: As the intervention has wound down, many contracts have come to an end. This process has required considerable planning and sensitivity to reduce the anxiety felt by staff.

 

ZAMSTAR: The prevalence surveys are an enormous challenge.  These are the largest surveys undertaken in the region, with more than 100,000 participants leading to more than 200,000 cultures in the 5 ZAMSTAR laboratories.  In the rural areas of Zambia, it is hard for the field teams to meet their daily targets, so they are being reinforced with additional staff.  In the urban areas, the targets are met more easily, but the laboratory can only handle a certain number of samples per day, and whenever there is a problem in the laboratory workflow, the field teams have to be asked to go slowly until it is resolved.  Maintaining quality at every step of the procedure is also a challenge and the lab team has already demonstrated that the newer MTB64 assays are not as specific as the ones that were used in the baseline surveys.  As a result we have had to alter our protocol for identification of isolates, which increases the workload still further and makes the laboratory work more expensive than originally projected unless we are able to get the costs of the test kits refunded.

As we reach the end of the fieldwork, many staff are worried about their future employment and are already looking for new jobs.  We are trying to manage the process by encouraging commitment and including incentives for completion of contracts.  Similarly the sites are anxious about what will happen when ZAMSTAR finishes, and this could threaten the good relationships that we now enjoy.

At the National level, the Zambian Ministry of Health is still undergoing investigations surrounding the use of donor funds, and this makes it harder to work with them on plans for the future.

In South Africa, there have been ongoing problems with violence and strikes, which can make it impossible for the field teams to carry out their duties.

 

Modeling Project:  See above. 

 

Lessons Learned

THRio:

1.     Importance of clinic staff.  THRio’s experience emphasizes the continued importance of clinic staff support for the overall project. Without support of the clinicians and nurses who 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.

2.     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 antiretrovirals, which does not require a clinical encounter. 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 affect 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.

3.     TB before HIV diagnosis.  A large proportion of TB cases continue to be detected before or at the time of HIV diagnosis, as patients are unaware of their status until they become ill.  Thus, an IPT intervention misses these individuals and fails to prevent these cases.  The key strategy for addressing this problem is promoting earlier diagnosis of HIV, at primary health clinics and in the community.  The Brazilian government has had several campaigns aimed at increasing the proportion of HIV-infected individuals who are tested and engaged in care, but much remains to be done to achieve this.  The City of Rio de Janeiro is promoting HIV testing throughout the city.

 

Thibela TB: Lessons learned from implementation of Thibela TB that we have reported this year are particularly drawn from our experience of initiating IPT among more than 24,000 individuals.

 

1.     Isoniazid is safe.  Data from the Thibela TB main study show that adverse effects of isoniazid are very rare. Despite a population with a relatively high median age (40 years) who would traditionally be considered at high risk of hepatotoxicity, only 17 individuals (0.07%) experienced symptoms suggesting symptomatic hepatotoxicity. Four events (two hepatotoxicity, one fatal, and two convulsions) fulfilled criteria for seriousness. Our data suggest that clinical criteria can safely be used for screening prior to and monitoring during IPT.

2.  Isoniazid is well tolerated.  Data from a detailed substudy of minor adverse effects among 498 Thibela TB enrollees show that IPT is very well tolerated. 324/498 (65.1%) reported feeling better on IPT: in 180/324 (55.6%), this was due to increased appetite. The prevalence of specific symptoms was low, with period prevalence during the first month of 9/162 (5.6%) for headache; 7/162 (4.3%) for itchy skin; 6/162 (3.7%) for joint pains; 3/162 (1.9%) for diarrhea; 3/162 (1.9%) for nausea and 2/162 (1.2%) for stomach pains. Overall, IPT was well tolerated by the great majority of individuals in this trial. Increased appetite was frequently reported; while this was viewed positively by most, it has potential to adversely affect adherence in settings of food scarcity.

3.   Screening for active TB prior to IPT contributes to TB case finding.  Data from TB screening at enrollment of almost 26,000 individuals to the Thibela TB intervention showed that 365 (1.4%) had definite or probable tuberculosis. Compared with screening by symptoms alone, screening by symptoms plus chest radiography increased the number of definite tuberculosis cases detected by 2.6 fold. We learned from this that TB screening prior to IPT detects a substantial burden of tuberculosis and contributes to intensified tuberculosis case finding, and that in our setting, chest radiography is a useful addition to a symptom screen.

4.  Risk factors for active TB missed at screening  Among nearly 20,000 individuals screened at enrollment to Thibela TB who were considered not to have active TB and therefore were dispensed isoniazid, 48 (0.24%) were classified as TB screening failures, in that TB was diagnosed within three months of enrolment. Being in HIV care (odds ratio [OR]=4.33, 95%CI 1.66-11.3), lower weight (OR assuming linear effect=0.5, 95%CI 0.3-0.83) and alcohol use (OR=2.72, 95%CI 1.43-5.18) were associated with increased risk of TB being missed at screening. We learnt from this that our screening protocol missed very few cases, supporting the use of symptom and chest radiographic screening to exclude TB prior to starting IPT.

Some of these data have already been presented at conferences, and the work on adverse events will be presented at the World Lung Health conference in Berlin, November 2010. We have written up articles on these topics for a special supplement of the journal AIDS which showcases experience with IPT from all three of the CREATE projects. In addition, we have submitted three further articles for this supplement based on work within our HIV care program; these comprise a qualitative study of clinician and patient barriers to implementation of IPT; an observational study showing an association between IPT started around the time of ART start and reduced mortality, and a viewpoint discussing why randomized controlled trials may have underestimated the potential effect of IPT programs on mortality among people with HIV.

5. Isoniazid resistance among TB cases in individuals previously exposed to IPT.  This substudy of Thibela TB, with results suggesting no excess of isoniazid resistance among cases occurring after IPT, has now been published in AIDS.

6.  MGIT demonstration project: We have previously reported results from our MGIT demonstration project, showing the MGIT produces results faster than LJ and has higher yield, although the additional cultures which were positive on MGIT but negative on LJ were predominantly non-tuberculous mycobacteria. In ongoing work, we are investigating the clinical significance of these non-tuberculous mycobacterial isolates.

Cost effectiveness analysis reveals that the incremental cost per additional M. tuberculosis isolate generated using MGIT (or MGIT plus LJ) vs. LJ alone is highly dependent on the method used for species identification (cording and MPB64 being highly accurate and much less costly than standard biochemical tests); and on the proportion of MGIT cultures which are contaminated. These data highlight the importance of minimizing contamination rates with MGIT.  These data are in press with the International Journal of Tuberculosis and Lung Disease.

7.   Rapid detection of rifampin resistance.  Following on from the MGIT demonstration study, we are investigating optimal strategies for the detection of rifampin-resistant isolates, comparing the Hain MDRTB plus assay, used direct on sputum, to MGIT plus standard drug susceptibility testing.  Preliminary experience suggests that the Hain assay performs very well on smear positive specimens, but the sensitivity on smear negative specimens is much poorer, being less than 50%.

 

ZAMSTAR:  Overall, there has been a huge sense of achievement within the ZAMSTAR project.  However, as the project approaches its final year, and with the immense stresses of the final prevalence survey, we have learned (yet again) that everything on this scale takes longer than expected.  The teams have not had enough senior staff so that the principal investigators have been stretched too thinly.  On the other hand, the ZAMSTAR staff testify, whenever asked, to the benefits that they have received in terms of personal development as well as continuous employment in a difficult economic environment.

 

The following are the major lessons learned in the PAC Unit over the past year:

1. Radio remains the most influential media continuum for reaching the largest amount of the population in Zambia.
2. The Zambian Government (Ministry of Health) is more receptive to mutually cooperative initiatives as opposed to reactive “advocacy” campaigning.
3. The “research environment” in the country is still highly sensitive due to the negative publicity surrounding the MDP study carried out in the Southern Province of Zambia; it is still to be seen what kind of effect this will have on future research in the country.
4. Efforts to publicize the work of the organization (ZAMBART) and its major study (ZAMSTAR) through (national, regional and international) networking, media advocacy and sustained and strategic distribution of IEC materials have proven successful.

 

Unexpected Results. 

THRio: A large proportion (42%) of TB cases detected during the THRio follow-up period was diagnosed among patients first presenting with HIV. The THRio intervention is unable to help prevent TB in these patients unless HIV is diagnosed earlier. Almost 20% of all HIV-infected patients in the THRio cohort were diagnosed with TB upon entry.

 

ZAMSTAR: In Zambia, the minilabs established for the prevalence survey have stimulated a huge amount of interest within the country, with the donors and with other partners. The ZAMSTAR team is now working with FIND and other partners to commission similar laboratories in other countries.

The South African Department of Health is also asking ZAMSTAR to add hypertension screening to the prevalence survey, reinforcing the acceptability of these large representative surveys to inform policy and planning in both countries. 

 

Progress in Achieving a Global Access Strategy.

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. Thibela TB's investigators have contributed to transformation of global policy in two particularly notable areas:

 

1. Policy on screening for active TB prior to IPT

A major obstacle to wider implementation of IPT has been the lack of an evidence-based policy on the most appropriate screening tool to exclude active TB prior to starting IPT. We have contributed two datasets to a meta-analysis led by WHO using individual patient data which addresses this question, and recommends a four symptom screening tool which has high sensitivity and good negative predictive value in most populations. A paper describing this meta-analysis has been submitted to PLoS Medicine.

 

2. Revised WHO guidelines on IPT

Thibela TB investigators participated in the meeting to revise these guidelines in January 2010. The revised guidelines, currently under wider review, seek to remove obstacles to IPT implementation.

 

3. Contributing to global advocacy efforts

This year our principal contributions to global advocacy for the wider use of IPT include:

 

Disseminating our experience in IPT implementation in a supplement in a high-impact journal

We have contributed 8 articles to the CREATE special supplement on IPT i which will be published in AIDS later this year. These articles primarily describe our lessons learned in widescale IPT implementation, as described in the lessons learned section above.

 

Disseminating our experience at international meetings

We have presented our work at a number of international meetings.  Particular highlights have included the WHO/IAS/CREATE-sponsored meeting on TB/HIV research priorities prior to the International AIDS Society meeting in Cape Town, July 2009, which attracted an audience of TB and HIV experts from around the world. We presented a summary of our experience in IPT implementation.

At CROI 2010, in addition to our abstract presentations, we were invited participants in a WHO-organized TB/HIV satellite meeting, where we made presentations on the association between IPT and reduced early mortality in our ART programme, and on the use of IPT in settings of drug resistant TB.

At the WHO/ILO expert consultation in October 2009 on TB in the workplace, we were invited to share our experiences, particularly of Thibela TB.

At the 2^nd South African TB conference, with more than 1,800 delegates from 20 African countries, we shared the lessons learnt from Thibela and contribute to the writing of the Conference resolutions which called for scaling up of intensified case finding and IPT.

At the upcoming World AIDS Conference in Vienna, July 2010, we will participate in a WHO satellite meeting, Accelerating the implementation of collaborative TB/HIV activities in the WHO European Region, making a presentation on the implications of drug-resistant TB for IPT roll-out.

 

TB HIV integration

We are coordinating a review of the integration of TB/HIV services at facility level in low and middle-income countries which has been commissioned as a background paper for the upcoming First Global Symposium on Health Systems in Montreux, November 2010.  This will give an opportunity to highlight IPT implementation as a key outcome of TB/HIV service integration.

 

ZAMSTAR.

ZAMSTAR and the broader teams in ZAMBART and DTTC continue to work towards improving access for ICF, IPT and Infection control.  In South Africa, DTTC has completed a survey of risks to healthcare workers across the country and is raising the profile of IC needs and possible interventions.  In both countries, HIV registers and VCT procedures have been updated to include routine screening for TB through symptom screening.  In Zambia, the IPT pilot is ongoing in ZAMSTAR sites and several thousand people have now started on treatment with good adherence as measured in the registers.

At the international level, the ZAMSTAR team are regular contributors at WHO and other meetings that aim to promote the 3i's policy.  For instance several of us were involved in the GRADE Expert group to finalise the WHO recommendations on IPT and ICF that are currently being released.  We have also been closely involved in other guideline setting meetings around prevalence surveys (the so-called "Red Book") and the guidelines for Interferon Gamma-release assays and serodiagnostics, both of which refer to the potential use for detecting and treating latent tuberculosis as well as active disease.

 

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

 

CREATE PAC Report

This was a productive year for the CREATE Policy and Advocacy Core with increased focus on three I’s implementation and transforming PAC work into delivery.  Globally, CREATE investigators contributed to development of World Health Organization policies and practice guidelines for both IPT and ICF, using data and experience from CREATE studies.  PAC contributed to the content of the South African Department of Health’s new IPT guidelines, making South Africa the first country to adopt the WHO 4-item screening questions in IPT guidelines.  This year the Brazil Department of Health distributed a federal Letter of Notification recommending that implementation of IPT be managed by HIV clinics.   THRio’s research was cited in this Letter. 

Please note that some material in this section is duplicative.  This has been done intentionally so that the PAC section can be viewed as a stand-alone section.

 

PAC Objective 1. Create and maintain and accommodating environment for conducting and concluding the studies.

 

Global PAC

• CREATE videos are completed with the addition of a Portuguese translation of the THRio video for use in Brazil and Lusophone countries and a 10 minute overall video of CREATE.  These have been distributed through the network of CREATE project, to respective Ministries of Health, and to advocates and journalists.  They are also posted on YouTube and Facebook.   

http://vimeo.com/11655393

http://www.youtube.com/watch?v=lCVpFa5VScY

http://www.youtube.com/watch?v=talpDunG6Es

• Other CREATE communications:  The quarterly CREATE PAC Newsletter highlighting CREATE’S accomplishments is distributed to several hundred organizations.  CREATE PAC Bulletins are distributed bimonthly to TB/HIV NGO collaborators.  The website continues to be used as a TB/HIV resource and as a resource for CREATE scientific articles.

http://www.tbhiv-create.org/sites/default/files/Newsletter_JUNE2010_0.pdf

http://www.tbhiv-create.org/sites/default/files/PAC_JUNE2010.pdf

• CREATE was presented in the following meetings and presentations

• Plenary Speaker.  Brazil national TB conference. Controlling TB Related HIV.  May 2010.  (Richard Chaisson)
• Plenary Speaker.   TB and HIV Research: What is it and What Ails It.  World Health Organization Meeting, International Union against TB and Lung Disease, Cancun, Mexico 2009  (Lois Eldred)
• Rapporteur, Community Involvement in TB Drug Development. 2^nd annual South Africa TB Conference 2010, Engaging Community in TB research (Gavin Churchyard,  Lois Eldred)
• The CREATE Experience:  From Research to Implementation.  2^nd Annual South African TB Conference 2010 (Lois Eldred,  Nulda Beyers, Gavin Churchyard, Haileyesus Getahun)

 

THRio

THRio was well- represented at the Brazil National TB Conference….

•       THRio is publishing a quarterly newsletter to share study progress and results in Rio and at the national level

 

Thibela

Thibela investigators met at least once with representatives from the National Health and Safety Committee of the National Union of Mineworkers, National Department of Mineral and Resources, Department of Health and the mining companies to brief them on progress and solicit their ongoing support for the study.    

• Presentations on Thibela TB were presented at the following conferences and workshops

o    TB and Mines Symposium,  2^nd  Annual South Africa TB Conference 2010

o    Conducting Community-Based Research,  2^nd  Annual South Africa TB Conference 2010

o    Preventing TB in silica exposes workers. COPICON, SA 2009

o    Controlling TB in high HIV prevalent settings. SA Chamber of Mines TB Workshop 2009 (Churchyard 2009)

• The Thibela PI (Churchyard) used his experiences from Thibela  in the following:

o    National Committee on TB and the mines

o    NIOH TB in the mines workshop, 2010

o    Review of National Guidance note for TB in the mining industry 2010

o    Round 10 Global Fund: “TB in the mines” gap analysis, 2010

 

ZAMSTAR

• Core group of Zambian national journalists trained on TB and HIV; output of this training entailed a three-part radio programme series on TB; four articles in national newspapers on TB stigma, TB/HIV and the Three I’s; and one other one-off radio programme on the evolving role of home-based care in the era of ART.

• Zambian HIV activists (citizen journalists as part of International HIV/AIDS Alliance’s Key Correspondents group) trained on TB basics, the TB/HIV relationship and ‘Three I’s’ to improve first-hand reporting of the epidemics.
• Zambian HIV activists (a mix of major civil society organizations) trained in TB basics, TB/HIV and the ZAMSTAR Study; the group also participated in national-level World AIDS Day commemorations in Lusaka by handing out IEC materials on the ‘Three I’s’.
• Fifty media (national and international) mentions about ZAMBART/ZAMSTAR from March – December 2009.
• Quarterly newsletter created to inform staff and key stakeholders about the work of the organization (began December 2009).
• First-ever ZAMBART Annual Report (2009) written, published and disseminated to key national, regional and international-level stakeholders.
• Eleven-week long public health radio programme series held on Zambia’s widest reaching radio station covering 4.4 million listeners; ZAMBART researchers discussed TB basics, the ZAMSTAR Study, the Three I’s, TB stigma and the TB/HIV relationship among many other topics.
• Three-part video drama-documentary series (20 minutes each) filmed on TB basics, the TB/HIV relationship and the ZAMSTAR Study for broadcast on national television and for use in Zambian health clinics (for patients waiting for care).
• Networking within Zambian Civil Society: Researchers-Reporters group (ZAMBART & CIDRZ founder members); Civil Society Health Forum (Oxfam & Swedish Embassy key organizers).
• Openings and public events with key stakeholders (primarily the Ministry of Health): TB diagnostic area and digital x-ray machine opening (attended by the Zambian Health Minister) in Lusaka’s Kanyama Clinic and ZamLab CTLs official openings in Lusaka (attended by the Zambian Health Ministry Permanent Secretary and head of its National TB Programme), Livingstone, Kabwe and Ndola.

 

PAC Objective 2. Transform national policies and practice for controlling HIV-related TB

 

Global PAC.  

Global PAC developed the Case-Based Curriculum on the Three I’s, an implementation guide based on CREATE experiences.  In addition to cases illustrating the Three I’s in the CREATE studies, there are cases based on additional programs in South Africa, as well as Namibia, and Rwanda.  The curriculum is primarily targeted to clinics providing HIV care, but includes sections on TB/HIV integration as well.   We are in discussion with Elizabeth Glaser AIDS Foundation, I-TECH and other NGO’s in providing training (see Delivery Section of report).

Global PAC and Thibela developed a pocket guide for South African clinicians.  The two sided guide provides diagnostic algorithms: Preventing TB in HIV-Infected Patients: Isoniazid Preventive Therapy and Screening HIV-Infected Patients for TB: Intensified Case Finding. It

Follows the recently released South African National IPT Guidelines and is intended for care of HIV-infected patients at voluntary counseling and testing centres, pre-ART and wellness centres, antenatal/PMTCT Clinics, ART Clinics and hospitals.  It can also be used for all contacts of TB patients. The Rio de Janeiro municipal secretariat adapted the guide to meet Brazilian standards and translated it into Portuguese for use within the city. The guide was distributed to Russian and Central Asian countries as part of the TB/HIV Working Group Meeting in Almaty, Kazakhstan and Uzbekistan is interested in translating it into Russian to use as an example of how IPT can be simply implemented.  The guide was also distributed to SA provincial TB program managers, Kenyan and Nigerian HIV NGO’s and the Philippine Department of Health at the IAS Conference in Vienna.

 

THRio

• THRio has produced new educational printed materials targeted at health care workers and civil society.    
• The Brazil Dept of Health issued a Letter of Notification, citing the 2007 publication by Golub and colleagues.    The Letter delineates that HIV practitioners (not TB control programs) are responsible for implementing IPT.   Also, new ART registration forms used to request ART medications from the DOH, now have a check-off for “Screened for TB” and “Initiated IPT”.  Both of these national actions are a direct result of CREATE.
• THRio serves as the Coordinator of the TB Working Group of the Health Secretariat of Rio de Janeiro and state and federal partners.

 

Thibela: 

Lessons learned from implementation of Thibela TB are particularly drawn from the experience of initiating IPT among more than 24000 individuals. We have presented these lessons learnt at the South African AIDS and TB conferences, South African Thoracic Society conference, Mine Medical Practitioners Conference and workshops convened by the Chamber of Mines, Department of Minerals and Resources and the Department of Health.  Of particular note, at the 2^nd South African TB conference, with more than 1,800 delegates from 20 African countries, we shared the lessons learnt from Thibela TB and contributed to the writing of the Conference resolutions, which called for scaling up of intensified case finding and IPT.

 

The key lessons learnt that have been presented at the various conferences and meetings include these:

• Isoniazid is safe
• Isoniazid is well tolerated
• Symptom and chest radiographic screening prior to starting IPT misses few cases of TB
• There is no excess isoniazid resistance among TB cases in individuals previously exposed to IPT
• MGIT produces results faster than LJ and has higher yield

 

Thibela TB and CREATE partners hosted a meeting with the National Department of Health and other key stakeholder to finalize the South African guidelines for tuberculosis preventive therapy  among HIV infected individuals. The Thibela TB / CREATE team provided major input that resulted in South Africa being the first country to adopt new WHO IPT guidelines. The guidelines have been distributed and implementation started. The target is to start 60,000 eligible HIV-infected persons on IPT over the next year.  Thibela TB has achieved its goal of transforming national policy on intensified case finding and isoniazid preventive therapy.

The Aurum Institute is actively involved in planning and informing South Africa’s Round 10 application to the Global Fund Against AIDS, TB and Malaria (GFATM) which is due in August 2010.  Aurum wrote the Gap analysis on isoniazid preventive therapy and intensified case finding for Round 10. At a recent Global Fund Round 10 meeting the proposed focus for the Round 10 Global Fund application is to scale up integration of TB and HIV activities at the primary health and community levels, particularly of IPT, ICF, ART, HIV Counseling and testing and male circumcision. If the Round 10 Global Fund proposal is awarded, this will result in major scaling up of delivery of IPT and ICF in South Africa.

 

ZAMSTAR

• ZAMSTAR met with Zambian MOH officials to update them on ZAMSTAR progress.

• ZAMBART staff participates in technical committees aimed at creating policies and guidelines needed to improve public health within the country, including TB/HIV collaborative care, IPT and Enhanced TB Case Finding.
•  Members of ZAMBART staff are currently drafting an Enhanced Case Finding (ECF) user manual for government, medical professionals, organizations and individuals.

 

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

 

Global PAC:  Global PAC continues to work on training advocates to understand and promote sound TB policies.   These efforts have focused on training TB advocates internationally on research fundamentals and on implementing the Three I’s.  Research Fundamentals for Advocates, workbook for TB advocates was launched at the IUATLD Meeting in Cancun Mexico, 2009.   This 60 page publication is a collaborative effort of CREATE and TAG and the first of its kind.  It is distributed through the CREATE website and posted on the Global  Health Council’s TB Roundtable, the STOP TB and TAG TB Research listserves.   It has been used for advocacy trainings through TAG and ARASA.  For the full workbook see:

http://www.tbhiv-create.org/sites/default/files/ResearchFundamentals%5Bofficialversion%5D.pdf.

Global PAC also developed a campaign to educate HIV advocates to “Ask about IPT”.   Using messages about staying well with HIV by preventing TB, this effort targets HIV activists who know about “staying well” by taking antiretroviral therapy, but may be unaware of “staying well” by preventing TB.  This message was launched as the Global Village at the IAS Conference, July 2010. http://www.tbhiv-create.org/home/materials

 

THRio

As a consequence of THRio advocacy, IPT, intensified case finding, and infection control are included in TB and HIV/AIDS guidelines and/or in the Brazil national agenda (e.g., NTP, NAP and PAHO).  We have also included IPT in Brazil’s Global Fund application. 

 

Thibela

Thibela TB's investigators have contributed to transformation of global policy in two particularly notable areas:

1. Policy on screening for active TB prior to IPT.   A major obstacle to wider implementation of IPT has been the lack of an evidence-based policy on the most appropriate screening tool to exclude active TB prior to starting IPT. We have contributed two datasets to a meta-analysis led by WHO using individual patient data which addresses this question, and recommends a four symptom screening tool which has high sensitivity and good negative predictive value in most populations. A paper describing this meta-analysis has been submitted to PLoS Medicine.
2. Revised WHO guidelines on IPT Thibela TB investigators participated in the meeting to revise these guidelines in January 2010. The revised guidelines, currently under wider review, seek to remove obstacles to IPT implementation. Thibela TB achieved its goal of transforming international policy on intensified case finding and IPT

 

 ZAMSTAR

• ZAMBART staff continues to participate in WHO technical working groups (e.g.Technical Working Group for TB Nutritional Guidelines)

 

PAC 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.

 

Global PAC

A special supplement to the journal AIDS focusing on CREATE experiences with IPT has been reviewed by the journal editors; we anticipate its publication in time for November 2010 CREATE annual meeting.  This includes experiences from all CREATE projects and should be instrumental in promoting wide-spread IPT.

Global PAC continues DC-based activities including participation in the Global Health Roundtable. Dr. Celine Gounder presented at the Senate Briefing for World TB Day, March 24, 2010 describing experiences in Malawi with inadequate TB laboratory infrastructure and advocating for full appropriation of USAID and other government TB funding.

 

Thibela

• Thibela focused on  contributions to global advocacy for the wider use of IPT including:

• Disseminating Thibela’s our experience in IPT implementation in a supplement in a high-impact journal

• We have contributed 8 articles to the CREATE special supplement on IPT implementation which will be published later this year. These articles primarily describe our lessons learned in wide scale IPT implementation, as described in the lessons learned section above.

• We have contributed to Global Advocacy through presentations at international meetings.  Particular highlights have included the WHO/IAS/CREATE-sponsored meeting on TB/HIV research priorities prior to the International AIDS Society meeting in Cape Town, July 2009, which attracted an audience of TB and HIV experts from around the world. We presented a summary of our experience in IPT implementation.

• At CROI 2010, in addition to our abstract presentations, we were invited participants in a WHO-organized TB/HIV satellite meeting, where we made presentations on the association between IPT and reduced early mortality in our ART programme, and on the use of IPT in settings of drug resistant TB.

• At the WHO/ILO expert consultation in October 2009 on TB in the workplace, we were invited to share our experiences, particularly of Thibela TB.

• Thibela participated in the WHO satellite meeting, Accelerating the implementation of collaborative TB/HIV activities in the WHO European Region preceding the IAS Conference in Vienna, making a presentation on the implications of drug-resistant TB for IPT roll-out.

• Thibela is coordinating a review of the integration of TB/HIV services at facility level in low and middle-income countries which has been commissioned as a background paper for the upcoming First Global Symposium on Health Systems in Montreux, November 2010.  This will give an opportunity to highlight IPT implementation as a key outcome of TB/HIV service integration.

 

ZAMSTAR

•  Presentations by ZAMBART staff at regional and international conferences (International AIDS Society Conference, July 2009; The Union World Conference, November 2009; DFID’s “Delivering Effective Healthcare for All”, March 2010).

 

World Health Organizations PAC activities

 I.          Major Activities & Milestones:  Describe progress made towards the objectives and major activities outlined in your original proposal. 

The PAC activity has mainly focused in promoting the higher visibility of TB/HIV in 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. 

The scale up of collaborative TB/HIV activities particularly HIV testing among TB patients has resulted in better data reported to WHO from countries that was used for better estimation of the global burden. By the end of 2008, there were an estimated 1.4 million people living with HIV and TB.  Preliminary data reported to WHO showed that globally in 2009, 1.6 million TB patients were tested for HIV and of the 442,341 TB patients found to be HIV positive, 264,436 were put on co-trimoxazole therapy (CPT) and 137,399 on anti-retroviral therapy. Over 1.7 million people living with HIV were screened for TB and of those people only 77539 were put onto isoniazid preventive therapy.

Advocacy activities were enhanced during the reporting period both globally and nationally and were focused on the Asia Pacific, European and Central Asian regions. HIV infection in these regions is in mainly concentrated in marginalized groups such as drug users, sex workers and prisoners who generally are with more difficulty in accessing HIV and TB services. In Europe the uptake of ART services is generally low and lower in drug users. In the last Universal access report European coverage of ART for those in need was 17% and for drug users up to 10% percent. The Global TB report 2010 showed that only 27% of estimated number of HIV related TB patients are detected and that only 16% of these were receiving ART in 2008. 

Advocacy efforts were aimed at enhancing the collaboration and interaction of the TB and HIV stakeholders who are traditionally working independently in a mutually exclusive way. It was also targeted at key TB stakeholders to increase implementation of HIV testing of TB patients, at HIV stakeholders in an effort to catalyze implementation of the Three Is, and at drug user networks and activists to ensure that they could advocate for integrated TB/HIV and drug user services and drug resistant TB and HIV which are all major issues affecting this region.

The global advocacy efforts were targeted in keeping the visibility of TB among HIV stakeholders including implementers, researchers and donors. The WHO and the TB/HIV Working Group networks were used to accomplish these key advocacy objectives both globally and nationally.

 

II.          Accomplishments:  List all significant accomplishments for this project over the past year, and relate them to the progress and milestones you expect to achieve in the next grant period. 

Increasing and maintaining visibility TB/HIV in international and regional fora

• UNAIDS engagement in TB/HIV increased.  The PAC group at WHO worked with the UNAIDS in order to ensure higher visibility of TB in the work of UNAIDS, which has now put TB/HIV as one of the ten priority areas for the Executive Director for 2010-2012. During the reporting period the collaboration between UNAIDS and Stop TB Partnership has reached a new level in which the two organizations have developed a memorandum of understanding of working together for the next two years in line with the priority areas of the UNAIDS. The PAC group played an instrumental role in the development of this memorandum of Understanding, which will be signed officially during the IAS Conference in July in Vienna linked with media activities.
• AIDS (July) 2010 Conference (July 18-23, Vienna Austria)

The PAC group at WHO worked together with IAS to ensure the visibility of TB during the XVIII International AIDS conference to be held in Vienna Austria, July 18-23, 2010. There will be more TB sessions (both abstract, poster, and non -abstract driven) and other activities (Stop TB booth, demonstration) in the Conference than ever before.  The PAC group was involved in the organisation of many of the sessions in particular the high level special session in which the UN Special Envoy to Stop TB Jorge Sampaio will be the keynote speaker along with the heads of UNAIDS and the Global Fund.  The PAC team developed the key TB/HIV messages during the conference and shared accordingly using different communication media. PAC will also conduct Meet The Expert sessions throughout the week in Vienna.

• Accelerating the implementation of collaborative TB/HIV activities in the WHO European Region (forthcoming 16-17,July 2010)

The objective of this meeting, which will be held in Vienna immediately preceding the XVIII International AIDS Conference, is to provide an opportunity to share experiences and best practices for enhanced advocacy, resource mobilization and accelerated implementation of collaborative TB/HIV activities within the context of the European region. This meeting will be attended by TB and AIDS programme managers from Eastern European and Central Asian countries and authorities from drug rehabilitation and prison services and partners working in the region and will help countries to ensure the coherent inclusion of key TB /HIV activities through policy and programme changes into national strategic and operational plans.

• Workshop to build the capacity of civil society to accelerate advocacy on TB/HIV (July 15, 2010 Vienna Austria)

The forthcoming Training workshop to build the capacity of HIV activists to work on TB will highlight the TB/HIV collaborative activities policy which national TB and HIV programs must implement in order to respond to TB/HIV co-infection. The workshop increased participants' knowledge of the issues and their capacity to effectively engage in advocating for those services which reduce the burden of TB in people living with HIV, raise awareness and visibility of the key issues at all levels as well as creating demand for services locally.

• The TB/HIV Core Group meeting in Almaty, Kazakhstan. The TB/HIV Core Group conducted its regular special meeting in Almaty, Kazakhstan with an objective of using it as an advocacy opportunity for the central Asia region. The meeting was attended by AIDS and TB programme managers, NGOs and US Government partners working in the region in addition to the membership of the Core group. Programme mangers from Kazakhstan, Tajikistan, Uzbekistan and Kyrgyzstan attended the meeting and key issues peculiar to the region that require a follow up advocacy activity were identified as part of the continuum of advocacy efforts of the PAC.
• Drug User Networks Activist training (June 2010) 

In collaboration with the International Network of People who Use Drugs (INPUD), HIT, UNAIDS and Treatment Action Group a second workshop to build the capacity of drug users networks to work on TB/HIV was conducted. The two day advocacy workshop familiarized participants with the WHO integrated TB/HIV and harm reduction policy guide to address the problem of HIV associated TB among PUDs, and how to catalyze implementation in countries with drug use problems which is critical to the health of PUDs and contributes towards universal access of TB and HIV services for people living with HIV. The workshop held in Liverpool, UK from June 10-11, 2010 was highly interactive and participants developed a better understanding of the concerns and needs of the community of people who use drugs around TB and HIV and how best to respond to these needs. It also gave those attending an opportunity to network with each other and built momentum to catalyze implementation of a fully integrated approach based on the needs of people who use drugs in their countries and regions. The next steps are to develop strategies to enhance community mobilization for implementation of collaborative TB/HIV and drug user services and demand generation for the services

• Conference on Opportunistic Infections and Retroviruses (February 2010)
  The Stop TB Department of WHO in collaboration with the Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE) organized a meeting affiliated with the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) in San Francisco, USA. This is the fourth in a series of meetings organized since 2007.The meetings have successfully raised the profile of HIV/TB among HIV researchers in particular by sharing data from ongoing studies, identifying research gaps and stimulating further HIV/TB research. The meeting at CROI 2010 promoted high level scientific interchange of ideas and research priorities leading to a better understanding of the magnitude and burden of TB (including drug resistant strains) especially in HIV prevalent settings.
• From Mekong to Bali: scale up of HIV/TB collaborative activities in Asia Pacific (August 2009)
  Catalyzing the implementation of collaborative HIV/TB activities in the Asia and Pacific regions was a key priority in 2009. This region has more than half of the global burden of TB and 12% of the global burden of HIV. To this end this meeting was organized by the World Health Organization (WHO) in collaboration with the HIV/TB Working Group of the Stop TB Partnership. 127 people from 18 countries participated in the meeting with representation from all high TB and HIV burden countries. Participants shared experiences and best practices to inform plans to accelerate the implementation of nation-wide scale up of collaborative HIV/TB activities. The meeting followed on from the first regional HIV/TB meeting held in the Mekong sub region in Ho Chi Minh City, Vietnam in October 2004. National TB and HIV program managers were joined by a broad range of AIDS and TB stakeholders active in the Asia and Pacific regions, members of the HIV/TB Working Group and representatives of bilateral and multilateral organizations, NGOS, and faith based organizations. The presentations and posters from the meeting are available below. The final meeting report is available at: http://www.stoptb.org/wg/tb_hiv/meetings_2009.asp.

 

Key communications

The PAC at WHO provided technical assistance to community groups, TB/HIV activist groups, and the broader civil society such as Oxfam, Action Aid, Act Up Paris, ITPC, EATG, GNP+, SEA-AIDS and HDN networks, to ensure they are informed and work towards scaling up the implementation of the 12 collaborative activities. PAC engaged new NGOs in TB/HIV work including the private sector. Worked with the Global Business Coalition on TB/HIV and held a TB/HIV specific GBC Coalition Call where members come together to discuss key issues. They Worked with NGOs such as the World AIDS Campaign which resulted in a section on TB/HIV on their website.

In collaboration with the HIV Department and UNAIDS, developed and produced a brochure on the Three Is titled No more people living with HIV dying of TB. Hard copies were disseminated at the STP Forum and it is available on line on both the WHO and WG websites.

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.

Together with AIDSMAP developed a newsletter specifically about TB/HIV which was distributed to 30,000 HIV implementers and decision makers.  

 

IV.        Challenges: Discuss how you have dealt with the anticipated challenges described in your grant proposal. Have there been any additional internal or external challenges? How were they addressed?  What challenges do you foresee in the next year? Is there anything the foundation can do to assist you?

Challenges: Key challenges are the need to link and transfer the CREATE country level work to influence local policy and implementation. Although some progress has been registered particularly in South Africa while CREATE counterparts and PAC worked together to influence the adoption of the new WHO IPT and ICF policy, it remains a problem in Brazil and Zambia. Discussion is being initiated and is going on in order to enhance the contribution of CREATE partners to influence policy and programme contribution in Brazil. Zambia is the only country with no supportive policy of IPT among the CREATE countries remain the challenge to improve the policy and programme environment for IPT and ICF.

WHO CREATE PAC Plans for the 2010-2011 

CREATE is conducting a media training on implementation of IPT in concert with the 2010 annual meeting in Cape Town.  Journalists have been identified through our PAC teams in South African and Zambia.  We anticipate that the AIDS IPT supplement will be launched at the annual meeting and the supplement will highlight CREATE results to date with IPT. It will also serve as preparation for dissemination of the final study outcomes.

CREATE PAC and Delivery are working cohesively to promote delivery. Case-based curricula and training for three I’s implementation are planned for the coming year.  PAC will continue to work collaboratively with its partners to maximize impact and effectiveness of advocacy work and increase the reach of activities.

 

Delivery Update

 

Global

CREATE has been working with implementers in sub-Saharan Africa – including the PEPFAR-funded TSEHAI in Ethiopia; Malawi-Liverpool-Wellcome Trust (MLW), Médecins Sans Frontières (MSF) and the Ministry of Health in Malawi; the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) and the Ministry of Health and Social Welfare in Lesotho; the Centers for Disease Control and Prevention (CDC) in Botswana; and the World Health Organization (WHO) and Department of Health in Swaziland – to scale up active and intensified TB case-finding (ACF and ICF) and isoniazid preventive therapy (IPT).

CREATE is working with TSEHAI to establish a community-based ACF program in Gambella and Benishangul Gumuz regions in western Ethiopia. In January, CREATE organized a meeting of TSEHAI, the Ethiopian Health and Nutrition Research Institute, the Foundation for Innovative New Diagnostics (FIND), CDC and WHO to discuss the case-finding program and need for regional laboratory strengthening. Regional labs will be established for each region to perform sputum smear microscopy and mycobacterial culture using MGIT. FIND has committed to providing reagents and other consumables for the regional labs. TSHEAI has obtained approval from CDC to utilize roll over funds from FY 2008 to fund this project. CREATE and TSEHAI are now moving forward with plans to establish the regional labs and to train Health Extension Workers supporting DOTS to also conduct ACF in the communities that they serve.

CREATE is collaborating with MLW, MSF and the Ministry of Health to pilot ICF and IPT in Thyolo District in southern Malawi. The Ministry of Health current recommends IPT for children <5 year of age who are contacts of active TB cases, and plans to implement IPT among HIV-infected persons, but is looking to CREATE, MLW and MSF to provide evidence on how best to scale up ICF and IPT in Malawi countrywide. CREATE and MLW submitted an application for an NIH R01 grant to fund a study of different algorithms for TB case-finding and exclusion.

CREATE is working with EGPAF and the Ministry of Health and Social Welfare in Lesotho to scale up ACF and IPT among women presenting for antenatal and postnatal care, HIV- and/or TB-exposed infants, and household contacts of active TB patients identified among women and infants in pregnancy and the postnatal period. CREATE has met with Director General for Health, the Director of the STI/HIV and AIDS Directorate, the Manager of the National TB Program, the Director of Laboratory Services, the Manager of TB Labs to line up support for ACF and IPT in the country, with a specific focus on pregnant women and infants. CREATE has also met with local implementers including the International Center for AIDS Care and Treatment Programs (ICAP), the Clinton Foundation, Partners in Health and the Lesotho Network of AIDS Service Organizations to assess the baseline situation and line up additional political support for its plans. CREATE is now working with FIND and the Ministry of Health and Social Welfare to strengthen its laboratory capacity.  CREATE and EGPAF are also applying for an NIH R01 grant to fund implementation research on to study the burden of, screening and diagnostic tools for, and impact on MTCT of HIV of undiagnosed pulmonary TB among Basotho women during pregnancy and postpartum; the incidence of adverse events related to IPT among HIV-infected Basotho pregnant women and HIV- or TB-exposed infants in whom TB has been excluded; and the burden of HIV and undiagnosed pulmonary TB among household contacts of Basotho women diagnosed with TB during the antenatal and postpartum periods.

CREATE is working with CDC Botswana to develop a community-based ACF program. CREATE gave a presentation on the evidence for ACF to the Botswana Ministry of Health and other local non-governmental organizations working in Botswana. Based on the initial feedback of the national Director for Communicable Diseases and the National TB Program Manager, CREATE and CDC Botswana are planning a baseline TB prevalence survey, a household TB case-finding program, and an enhanced TB case-finding program. CREATE and CDC Botswana plan to apply for an NIH R01 implementation research grant to compare household-based TB case-finding and enhanced TB case-finding, with a specific focus on the cost-effectiveness of each approach in various districts in Botswana.

CREATE is collaborating with WHO and the Department of Health in Swaziland to scale up ICF and IPT in primary care clinics and public health units in Manzini. The National TB Program Manager in Swaziland has been very supportive of CREATE’s plans thus far, which include using a cough officer at the point of registration to identify both TB and HIV suspects, and triage them for TB screening and HIV counseling and testing. Funding for this initiative has not yet been identified.

CREATE set Deliverability targets for IPT and ICF in its 2009 Deliverability Report that were based on reasonable assumptions for uptake in the three countries where projects are underway and globally.  Progress towards these targets is shown in the Table 3 below, provisionally reported by the WHO and embargoed until November 10, 2010.  It is fair to say that the impact of CREATE on achieving progress with implementation has been substantial, particularly in South Africa and globally.

 

Table 3.  CREATE Targets for ICF and IPT in South Africa, Zambia, Brazil and globally with WHO Reported Uptake in 2009.

Region	Target for ICF coverage in 2012	PLWHA covered by ICF in 2009	Target for IPT coverage in 2012	PLWHA receiving IPT in 2009
Brazil	40,000	8668	4,000	Not reported
South Africa	200,000-500,000	433,662	38,500	23,583
Zambia	250,000-500,000	Not reported	1,000	Not reported
Globally	1,090,000-2,090,000	1,687,402	83,500	85,426

 

THRio

1.     Rolling out ICF and IPT through the Brazilian NTP and NAP

Based on evidence from the THRio Study, the Brazilian government prioritized provision of IPT in HIV clinics throughout Brazil. In late July 2009 the National AIDS Program issued a policy requiring HIV clinics to take responsibility for screening patients for active TB and providing IPT to TST-positive patients. The NAP has included IPT and other TB drugs in the SICLON, the system that controls drugs for treatment of HIV and opportunistic infections nationally. Drugs for TB prevention and treatment will have the same status, availability, and control in HIV clinics nationwide do antiretrovirals and medications to treat other opportunistic infections; this is a major leap forward in the integration of TB/HIV activities for the country.

The delay in initiation of IPT due to the requirement for a positive TST remains a challenge. The Brazilian government has disseminated THRio’s baseline results to encourage HIV clinics in Brazil to provide TST and IPT to all eligible HIV clinic patients. The current goal is to offer all patients attending HIV clinics a TST and IPT at their next clinic visit, which should achieve a steep escalation in use of IPT. THRio continues to study how best to deliver TST and IPT to HIV-infected persons using funding from the Brazilian National TB Program.

 

2.     Partnering with non-governmental organizations to roll out ICF and IPT nationally

THRio has partnered with GFATM-funded organizations to train health care providers working in HIV clinics throughout the country to prevent TB among HIV-infected patients. The THRio message “If you have HIV, take the TB test; if you have TB, take the HIV test.” is being disseminated in folders and placards that have been distributed to state and city health departments as part of training materials.

 

Thibela

 

1.     Collaboration with Ekurhuleni Metropolitan Municipality

With funding for a PEPFAR Public Health Evaluation (PHE), the Aurum Institute is collaborating with the Ekurhuleni Metropolitan Municipality to implement different models of ICF, IPT and infection control in eighteen clinics in the district. Eighteen primary care clinics will be selected and randomized to one of three interventions: The Three I’s strategy – ICF, IPT and infection control – with general health systems strengthening; provider-initiated TB screening and triaging plus general health systems strengthening; and general health systems strengthening alone.

One of the limitations of The Three I’s strategy is that it focuses on known HIV-infected persons who are enrolled in care. Most persons living with HIV/AIDS in South Africa are not aware of their HIV status and are not receiving care for HIV. The South African Human Sciences Research Council survey found that only 50.3% of the population had ever had an HIV test and knew their HIV status. For this reason, The Three I’s strategy will miss persons with undiagnosed HIV who are at high risk for TB. In addition, TB is highly prevalent in the general population in South Africa. Through provider-initiated TB screening, all individuals attending primary care clinics will be screened for TB regardless of the reason for presenting to the facility. TB suspects will undergo further testing for TB and will be triaged and fast-tracked. Through this PEPFAR PHE, the Aurum Institute will evaluate the relative impact of ICF among HIV-infected persons alone compared to ACF among all patients.

Protocols, project plans, training materials and implementation tools have been developed.  Study personnel have been employed and are currently conducting a situational analysis in order to get baseline data for the randomization to take place. Randomization and training is expected to be conducted in September 2010.

This project will also be rolled out to another district in South Africa due to a successful grant application to extend this project.

 

2.     Collaboration with Eastern Cape Province

Aurum has implemented ICF and IPT at Madwaleni Hospital, a small rural hospital in the Mbhashe District of the Eastern Cape Province. All those enrolled into the HIV Wellness program at Madwaleni Hospital are screened for signs and symptoms of TB during individual counselling sessions. Templates in patient files prompt recognition of danger signs, and the nurse mentor has the specific task of capacitating the nursing staff at the HIV clinic and primary healthcare centers throughout the District to identify TB suspects. HIV wellness clinic patients that qualify for IPT based on the WHO guidelines are offered IPT. HIV peer educators run HIV support groups at primary healthcare centers and deliver notification details of newly-diagnosed TB cases, thereby enhancing DOTS efforts at a clinic and community health worker level.

Sputum collection units have been placed outside the out-patient department and hospital wards to eradicate the ineffective, unhygienic practice of bedside sputum collection (using inappropriate containers), and thus improving infection control in health facilities. N95 masks have also been purchased for health care providers.

Data collection in the out-patient departments and hospital wards to strengthen TB-related indicators has historically been poor. A TB data collector and TB peer educators have been deployed to strengthen recording and reporting of TB-related data. Accurate and accessible data records for sputum AFB and culture results have been established, and allow for better TB suspect and case identification and follow-up.

 

3.     Screening household contracts of TB patients in Rustenburg

This project also known as the Ribolola (“digging deeper”) Project, modeled on the ZAMSTAR household intervention, is a partnership between Aurum and the North West Province Department of Health. The project was conducted within the Rustenburg sub-district municipality and aimed to screen the household contacts of patients who were identified with smear positive tuberculosis at eight primary health centers and the mining hospital. After index TB cases provide informed consent, a nurse visited the household to screen household contacts for symptoms of TB. Sputum was collected from TB suspects for smear and mycobacterial culture. Onsite HIV testing was offered to all participants ? 16 years of age and to participants ? 16 years who were TB suspects. Clients needing further investigation were referred to a public health facility.

Between 1 April 2009 to 31 March 2010, 709 index cases were recruited, 612(86%) of whom had subsequent household visits. Of 3,005 household contacts seen, 2,678 were adults and were screened symptomatically for TB. Sputum was obtained from 597 (22%) adult contacts. 81 (3.0%) of adult contacts were diagnosed with TB disease: 44 (54.3%) by culture, 16 (19.8%) by smear and 21(25.9%) based on clinical suspicion. 326 household contacts <5 years of age were referred to the public health services for TB exclusion and IPT prophylaxis. 176 (86%) of household contacts <5 years of age were started on INH prophylaxis, 15 were started on TB treatment, and 14 were lost to follow up.

Aurum has applied for additional funding to extend this program into two additional provinces and to evaluate the operational aspects of the program.

Aurum has seconded a professional nurse to the Rustenberg TB coordinator’s office to assist in managing the office. Aurum and the Rustenberg sub-district municipality are also finalizing details of an agreement for Aurum to provide 10 additional DOTS treatment supporters.

 

4.     TB/HIV integration in correctional facilities

Incarcerated individuals are at increased risk of contracting TB due to conditions within the prison such as overcrowding, poor ventilation and poor nutrition that promote the spread of TB. Aurum has a Memorandum of Understanding with the Department of Correctional Services in Johannesburg, Pretoria, Krugersdorp and Boksburg to support and strengthen the Antiretroviral Treatment Clinics in the correctional facilities. As part of Aurum’s work with the Department of Correctional Services, TB/HIV integration has been piloted at the Atteridgeville prison in Pretoria, and has now been rolled out to the other correctional facilities. The specific TB/HIV interventions that were implemented included: screening all new inmates for symptoms of TB; incarceration of sputum smear positive TB inmates separately from other inmates; appointing a TB focal person and TB/HIV committee at each facility; training nurses working in the correctional facilities on TB and infection control; and training peer educators working in the correctional facilities on TB

Between October 2009 and April 2010, 982 inmates were screened for TB on admission to the Attridgeville Prison. 69 HIV-infected inmates were screened for TB and 9 (13%) were currently on TB treatment. 190 HIV-infected inmates were offered co-trimoxazole preventive therapy and 30 were started on IPT.

Aurum has applied for funding to roll out this package of TB/HIV services and conduct operations research on this intervention at other correctional facilities in another region in South Africa.

Aurum is also conducting a TB prevalence study in the correctional facilities to measure the prevalence of TB, identify risk factors for TB and develop screening tools appropriate to this setting. Aurum is in discussions with Delft and Treat TB to include chest radiography as part of TB screening for all inmates annually.

 

5.     TB/HIV integration in commuting populations

The Emthonjeni Programme focuses on screening community members, particularly marginalized workers, at public transportation centers for HIV, TB and sexually transmitted infections. The Emthonjeni Programme targets taxi drivers; traders; workers in small- and medium-sized enterprises (SME’s); and farm, construction, mine and contract workers. There is an Emthonjeni team of counselors and nurses based in each of Burgersfort, Rustenburg and Klerksdorp, and three teams are based in inner city Johannesburg. A health center has been established at the taxi ranks in Johannesburg, where 5,000 taxi drivers and traders are based, and 500,000 commuters pass through daily. Two mobilizing officers recruit commuters, taxi drivers and traders for TB and STI symptom screening, and for HIV, hypertension and diabetes testing. HIV-infected individuals are referred if eligible for IPT and ART.

4,487 persons were tested for HIV and 6,280 were screened for TB at the taxi ranks in Johannesburg; 22% of those tested were HIV-infected, and 0.7% of those screened for TB were TB suspects. 4,704 persons were tested for HIV and 4,715 were screened for TB in Burgersfort; 9% of those tested were HIV-infected, and 0.4% of those screened for TB were TB suspects.

Taxi drivers with TB place commuters at risk. Taxi drivers are at risk because of exposure to commuters with TB. To this effect, as part of the Emthonjeni Programme, an intensified TB case finding project is to be implemented in August 2010 at the taxi ranks in Johannesburg for taxi drivers. The service offered will include an x-ray, full medical examination, sputum collection for smear microscopy and mycobacterial culture, and HIV testing.

 

6.     Increase TB/HIV integration among private practitioners

Since 2005 Aurum has been working with private practitioners to provide HIV services through approximately 50 general practices in a number of regions within South Africa. Over 21,000 patients have been enrolled onto HIV care programs, and over 9,000 started on ART. TB/HIV integration activities have been emphasized since the inception of this project, and regular training is provided on TB including intensified case-finding, treatment of TB among adults and children, isoniazid preventive therapy, and drug-resistant TB. Screening HIV-infected patients has recently been strengthened by improving access to TB investigations and changing data collection tools to ensure correct documentation of screening. Implementation of isoniazid preventive therapy has been slower than for other TB/HIV integration activities, but 1,919 patients have been started on INH. In 2010 the major activities undertaken to increase uptake of IPT included: improved access to chest radiographs as a TB investigation tool at GP sites; provision of INH by Aurum through PEPFAR funding at the Jade Square Clinic (which is now a Department of Health accredited facility); and mentoring on IPT by Aurum doctors seconded to public sector clinics.

 

7.     Improved infection control

Aurum is committed to improving TB infection control within all our partners’ facilities. As part of our plan, a TB infection control (TBIC) guideline was developed and distributed. A TB infection control training manual, program, and assessment tool have also been developed.

Between February and May 2010, a total of 15 sites (4 public sector, 6 private sector and 5 correctional) underwent a baseline assessment. Reports have been issued to all these sites and work is in progress with all this facilities towards improving their TBIC measures. A total of 53 staff members have been trained on TBIC from these sites, and these are staff members are responsible for caring for TB/HIV patients in their facilities. Aurum intends to roll out this intervention to all our partners within the next six months.

 

8.     Driving National Implementation of the Three I’s Strategy

Aurum is driving national implementation of The Three I’s strategy by educating, training and collaborating with the national and provincial Departments of Health, the national Department of Public Service and Administration, the national Department of Correctional Services, the South African National AIDS Council, PEPFAR, CDC, USAID, GFATM, Southern African HIV clinicians Society and academic societies such as the South African Thoracic Society and South African Infectious Disease Society.

In March 2010, a meeting was held to establish a partnership between the South African national Department of Health and CREATE to support the national roll out of intensified case-finding and isoniazid preventive therapy. The CREATE studies were presented, and discussions were held about the role of the CREATE in national scale up of The Three I’s. Mr Yogan Pillay (Deputy Director General for Health), Dr. Stella Anyangwe (WHO representative, South Africa office) and Dr. Kalpesh Rahevar (TB Medical Officer, WHO South Africa office) also attended the meeting.

Aurum has participated in a WHO review of the current national TB program, and in revising national Department of Health guidelines for TB prophylaxis among HIV-infected individuals; these guidelines are now being implemented. The new guidelines have removed the requirement for chest radiography and tuberculin skin tests prior to initiation of IPT, which is in accordance with WHO guidelines. In addition, INH is recommended for those with a previous history of TB, and states that ART is not a contraindication to IPT. Aurum participated in a number of training sessions held with staff from the national Department of Health and other public benefit organizations to assist in the scale-up of IPT. Aurum participates in all South African national Department of Health meetings on TB, and is consulting with Provincial Department of Health TB Directorates with regard to provincial TB operational plans, which are a direct response to the WHO review.

Aurum continues to work with the mining industry to scale up ICF and IPT programs in the occupational setting. Aurum addressed the annual Mine Medical Officer’s Association meeting on the topic of TB control in HIV-infected populations. Aurum developed the Lilly-GHI “Toolkit for an Integrated Approach to TB and HIV for Businesses in South Africa,” and has been involved in training on this Toolkit for businesses as well as government workplace programmes.

Aurum participated in the CREATE satellite symposium “CREATE: From Research to Delivery: Implementing Isoniazid Preventive Therapy and Intensified Case Finding in South Africa” at the 2^nd Southern African TB Conference in June 2010. Lessons learned from Thibela and other Aurum activities, as well as those from other CREATE projects, were shared with delegates at the conference.

Aurum is actively involved in planning and informing South Africa’s Round 10 application to the Global Fund Against AIDS, TB and Malaria (GFATM), which is due in August 2010. The proposed focus for the GFATM Round 10 proposal is the scale up of TB/HIV integrated activities at primary health facilities and at the community level, particularly IPT, ICF, ART, HIV counseling and testing, and male circumcision. If the Round 10 Global Fund proposal is awarded, this will result in major scaling up of delivery of ICF and IPT and ICF in South Africa.

 

ZAMSTAR Zambia

 

1.     Continuation and expansion of community-based HIV/TB case-finding in Zambia

ZAMBART has trained a cadre of staff who will continue to provide enhanced case-finding for TB (ECF). ZAMBART has signed a contract with the KNCV and TBCAP for US$130,000 to support these ECF activities.

ZAMBART has won funding from TB REACH to conduct ECF in the prisons and surrounding populations in collaboration with Centre for Infectious Disease Research in Zambia (CIDRZ), a PEPFAR-funded implementer in southern Zambia.

Through the EU-funded Strengthening TB, AIDS and Malaria Prevention Program (STAMPP), ZAMBART and partners CARE and the Kara Counseling and Training Trust have developed a training manual for household HIV and TB case-finding, and will be training an additional 100 household counselors to deliver ZAMSTAR-style household-based interventions outside of ZAMSTAR sites. This initiative is awaiting EU approval for its revised budget.

ZAMBART has also drafted a manual on how to conduct ECF, which is now being revised and edited, and is working on the WHO/KNCV “Red Book” on how to conduct TB prevalence surveys. These manuals will facilitate further dissemination of knowledge about and implementation of ECF and ACF.

 

ZAMSTAR South Africa

 

1.     Sustaining and scaling up clinic-based ICF/ECF and IPT in South Africa

The Desmond Tutu TB Centre (DTTC) has worked with the Western Cape Province to update and roll-out TB registers with HIV indicators, and VCT registers with TB indicators. The DTTC has trained health care workers on the use of these new registers. The new registers are now being utilized in all health care facilities in Cape Town and in most of the Western Cape Province. As a result of this effort, the City of Cape Town has now requested the DTTC to collaborate on writing a new centralized laboratory result management system for the city.

As a result of ZAMSTAR’s successes, PEPFAR has provided funding for external sputum booths to be placed at all 101 Cape Town TB clinics to allow for fast track diagnosis of TB suspects.

2.     PEPFAR-funded project to strengthen TB/HIV integration in South Africa

During the early phases of ZAMSTAR, the DTTC documented that there was poor collaboration between the TB and HIV services, which led to the launch of a PEPFAR-funded project on TB/HIV integration with three specific interventions: community and outreach VCT centers targeting males and young couples, health systems strengthening and linkages with maternal and child health programs. The PEPFAR funded community VCT sites have been made sustainable through linkages with non-governmental organizations.

 

3.     Improving occupational health and infection control in South Africa

The alarming incidence of TB in staff involved in the ZAMSTAR study prompted an increased focus on occupational health, and led to a USAID-funded study with the University Research Corporation on infection control in 150 clinics in 5 different provinces in South Africa. A high incidence of TB was documented in this study. Results of the study are currently being disseminated. The DTTC is collaborating with the South African Department of Health to plan and scale up TB infection control strategies in health care facilities.

4.     Dissemination of knowledge

Like ZAMBART the DTTC is working on the WHO/KNCV “Red Book” on how to conduct TB prevalence surveys. This manual will facilitate further dissemination of knowledge about and implementation of ACF.

 

5.     Implementation research

As a result of the DTTC’s experience in ZAMSTAR, DTTC is focusing research agenda on implementation research. The DTTC has been awarded funding by the IUATLD and TREAT TB to conduct implementation research on TB/HIV.

 

Plans for the Next Reporting Period

Year 7 of CREATE will see the analysis and presentation of the THRio study and ZAMSTAR.  Preliminary analyses for THRio will begin in September and be presented at the CREATE Annual Meeting in Cape Town. Results will also be submitted to the Retrovirus Conference in Boston in February and the IAS meeting in Madrid in July.  ZAMSTAR will finish its prevalence surveys in December and laboratory analyses in the first quarter of 2011, with presentation of results at the Madrid IAS meeting.  Thibela TB will continue with its prevalence surveys through June 2011 and begin analyzing results late in Year 7.

 

Appendix 1 - Publications

Recent Core Publications:

 

Sterling TR, Pham PA, Chaisson RE. HIV infection-related tuberculosis: clinical manifestations and treatment. Clin Infect Dis. 2010 May 15;50 Suppl

3:S223-30.

Chaisson RE, Churchyard GJ. Recurrent tuberculosis: relapse, reinfection, and HIV. J Infect Dis. 2010 Mar;201(5):653-5.

Pope DS, Atkins S, DeLuca AN, Hausler H, Hoosain E, Celentano DD, Chaisson RE. South African TB nurses' experiences of provider-initiated HIV counseling and testing in the Eastern Cape Province: a qualitative study. AIDS Care. 2010 Feb;22(2):238-45.

Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis. 2009 Dec;9(12):737-46. Review.

Shah M, Variava E, Holmes CB, Coppin A, Golub JE, McCallum J, Wong M, Luke B, Martin DJ, Chaisson RE, Dorman SE, Martinson NA. Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a High HIV prevalence setting. J Acquir Immune Defic Syndr. 2009 Oct 1;52(2):145-51.

Golub JE, Chaisson RE, Martinson NA. Additive effects of isoniazid preventive therapy and HAART. AIDS. 2009 Jul 17;23(11):1446-7.

Jee SH, Golub JE, Jo J, Park IS, Ohrr H, Samet JM. Smoking and risk of tuberculosis incidence, mortality, and recurrence in South Korean men and women. Am J Epidemiol. 2009 Dec 15;170(12):1478-85. Epub 2009 Nov 16.

Le Roux SM, Cotton MF, Golub JE, le Roux DM, Workman L, Zar HJ. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Med. 2009 Nov 3;7:67.

 

Recent Thibela TB Publications:

 

Outputs: Thibela generated

Publications in preparation

• Lewis JJC, Fielding KL, Grant AD, Chihota VN, Churchyard GJ. Eligibility for community-wide isoniazid preventive therapy in the South African gold mines. 2010. In preparation.
• Fielding KL, Grant AD, Hayes R, Godfrey-Faussett P, Chaisson RE, Corbett EL, Churchyard GJ. Thibela TB: design and methods of a cluster randomised trial of the effect of community-wide isoniazid preventive therapy on tuberculosis among gold miners in South Africa. Clin Trials. 2010

 

Publications submitted

• Churchyard GJ, Fielding KL,  Chihota VN, Hanifay Y, Lewis JJ, Grant AD. Risk factors for active tuberculosis missed at screening prior to starting isoniazid preventive therapy. AIDS, 2010.
• Mngadi K, van Halsema C, Luttig M, Fielding KL, Churchyard GJ, Grant AD. Tolerability and minor adverse effects during isoniazid preventive therapy among participants of a cluster randomised controlled trial in South Africa. AIDS. 2010
• Grant AD, Coetzee L, Fielding KL, Lewis JJ, Clark D, Churchyard GJ. “Team up against TB”: promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy among gold miners in South Africa. AIDS. 2010.
• Churchyard GJ, Lewis JJ, Grant AD , Chihota VN, Fielding KL. Symptom and chest radiographic screening for infectious tuberculosis prior to starting isoniazid preventive therapy: yield and risk factors for prevalent tuberculosis. AIDS. 2010.
• Barriers to implementation of isoniazid preventive therapy in HIV clinics: a qualitative study in South Africa. Lester R, Hamilton R, Charalambous S, Dwadwa T, Chandler C, Churchyard GJ, Grant AD. Barriers to implementation of isoniazid preventive therapy in HIV clinics: a qualitative study in South Africa. AIDS. 2010
• Eldred LJ, Churchyard GJ, Durovni B, Godfrey-Faussett P, Chaisson RE. Introduction to the Isoniazid Preventive Therapy for HIV-Infected People Supplement. AIDS. 2010
• Charalambous S, Grant AD,  Innes C Hoffmann C J, Dowdeswell R, Pienaar J, Fielding KL, Churchyard GJ. Association of isoniazid preventive therapy with lower early mortality in individuals on antiretroviral therapy in a workplace programme in South Africa. AIDS. 2010
• Grant AD, Fielding KL, Mngadi K, Churchyard GJ. Adverse events with isoniazid preventive therapy: experience from a large trial in South Africa. AIDS. 2010
• Why have IPT trials among people with HIV infection not demonstrated an effect on mortality? Grant AD, Fielding KL, Charalambous S, Chaisson RE, Churchyard GJ. AIDS. 2010

 

Publications in press

• Chihota VN, Grant AD, Fielding KL, Ndibongo B, van Zyl A, Muirhead D, Churchyard GJ. Mycobacterial Growth Indicator Tube compared with Löwenstein-Jensen medium in the investigation of pulmonary tuberculosis: performance and cost in a resource-constrained setting. Int J Tuberc Lung Dis. 2010. In press.

 

Published

• Hanifa Y, Grant AD, Lewis J, Corbett EL, Fielding K, Churchyard GJ. Prevalence of latent TB infection amongst gold miners in South Africa. Int J Tuberc Lung Dis.  2009;13:39-46.
• CL Van Halsema, KL Fielding, VN Chihota, EC Russell, JJC Lewis, GJ Churchyard, AD Grant. Tuberculosis outcomes and drug susceptibility in individuals exposed to isoniazid preventive therapy in a high HIV prevalence setting. AIDS. 2010.24:1051–1055.

 

Abstracts

5th IAS Conference on HIV Pathogenesis &Treatment, 2009

• CL van Halsema, et al. 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 no. MOPEB021

CROI, 2010

• CL van Halsema. The Effect of Antiretroviral Therapy on Tuberculosis Sputum Smear Status in HIV-Infected Individuals in South Africa

41^st Union World Conference on Lung Health, 2010

• AD Grant et al. Low risk of hepatotoxicity in a trial of community-wide isoniazid preventive therapy in South Africa
• CL van Halsema et al. Non-tuberculous mycobacteria in gold miners: evolving spectrum with increased HIV prevalence

 

Outputs: Thibela related

Publications submitted, under review

• H Getahun, W Kittikraisak, C Heilig, E Corbett, H Ayles, K Cain, A Grant, G Churchyard, M Kimerling, S Shah, S D Lawn, R Wood, G Maartens, R Granich, A Date, J K. Varma^. Development of a standardized screening rule for tuberculosis in people living with HIV in resource constrained settings: individual patient data meta-analysis. PLOS Medicine, 2010, under review.
• EL Corbett, T Bandason, T Duong, E Dauya, B Makamure, GJ Churchyard, BG Williams, SS Munyati, AE Butterworth, PR Mason, S Mungofa, RJ Hayes. Impact of periodic outreach diagnosis of symptomatic smear-positive disease on the control of infectious tuberculosis: a community randomised trial of two delivery strategies in Harare, Zimbabwe. Lancet. 2010.
• Ross J, Ehrlich RI, Hnizdo E, White N, Churchyard GJ. Accelerated lung function decline in gold miners following pulmonary tuberculosis. Thorax. 2010.
• Churchyard GJ, Fielding KL, Roux S, Corbett EL, Chaisson RE, De Cock KM, Hayes RJ, Grant AD. 12 versus 6-monthly radiological screening for the active case-finding of tuberculosis: a randomised controlled trial. Thorax. 2010

 

Publications in press

• K Middelkoop et al. Antiretroviral program associated with reduction in untreated prevalent tuberculosis in a South African township.Am Rev Respir Crit Care Med, 2010 (in press).

 

Published

• SD Lawn; R Wood; KM De Cock; GJ Churchyard. Complementary roles of antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in resource-limited settings. Lancet Infectious Disease. 2010.
• GJ Churchyard, G Friedland, K Fielding, E Nardell. Clinical trials of novel drugs for the treatment of multi- or extensively drug resistant tuberculosis infection: a public health and drug development opportunit. Lancet Infec Dis. 2010.
• BJ Marais, M Raviglione, PR Donald, AD Harries, AL Kritski, SM Graham, W El-Sadr, M Harrington, GJ Churchyard, SHE Kauffman, CJM Whitty, A Zumla. Scale-up of services and research priorities for TB diagnosis, management and control: Call to action. Lancet. 2010
• 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 in Zimbabwe: diagnostic value, and the effect of HIV status. Bulletin of the World Health Organization. 2010;88:13-21.
• RE Chaisson, GJ Churchyard. Recurrent Tuberculosis – Relapse, Re-infection and HIV. JID. Infect Dis,2010;201:653-5
• AD Grant et al on behalf of the United Kingdom Collaborative HIV Cohort Study group. Tuberculosis among people with HIV infection in the UK: opportunities for prevention?  AIDS 2009;23:2507-15.
• Lewis J, Charalambous S, Day JH, Fielding KL, Grant AD, Hayes RH, Corbett EL, Churchyard GJ. HIV infection does not affect active case finding of tuberculosis in South African gold miners. Am J Respir Crit Care Med. 2009;180:1271-8
• Park HH, Girdler-Brown BV, Churchyard GJ, White NW, Ehrlich RJ. Incidence of tuberculosis and HIV and progression of silicosis and lung function impairment among former Basotho gold miners. Am J Ind Med, 2009;52: 901-8  
• Churchyard GJ, Kaplan G, Fallows D, R Wallis, Onyebujoh P, Rook G. Advances in Immunotherapy for TuberculosisTreatment. Clin Chest Med. 2009;30:769-82
• Corbett EL,  Bandason T, Cheung YB, Makamure B, Dauya E, Munyati SS, Churchyard GJ, Williams BG, Butterworth AE, Mungofa S, Hayes RJ, Mason PR.^. Prevalent infectious tuberculosis in Harare, Zimbabwe: burden, risk factors and control implications. Int J Tuberc Lung Dis. 2009;13:1231-7.
• 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;374:921-33
• Chopra M, Lawn J, Sanders D, et al, for Th e Lancet South Africa team. Achieving the health Millennium Development Goals for South Africa: challenges and priorities. Lancet 2009; 374(9694): 1023-31.
• Th e Lancet South Africa Series Executive Summary core group. Writers Lawn JE, Kinney MV. The Lancet Health in South Africa: Executive Summary for the Series. August 2009.
• Lawn S, Churchyard GJ. Epidemiolgoy of HIV-associated TB. Current Opinion in HIV and AIDS. 2009; 4:325–333.
• 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.
• 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; 14:687-695.
  • Hoffmann CJ, Churchyard G. Pulmonary Tuberculosis in Adults, A Clinical Treatise, 1st Ed. Eds:  Zumla A, Schaaf HS.  Elsevier, 2009.

Book chapters

Guidelines

• Churchyard GJ [Contributor].  South African guidelines for Tuberculosis Preventive Therapy in HIV Infection. 2010. National Department of Health.

 

Abstracts

• Paper # 102. C Innes, S Charalambous, M Felix, K Fielding, A Grant, G Churchyard. Effectiveness of Isoniazid Preventive Therapy in Reducing Mortality in Patients on ART. 17^th Conference on Retroviruses and Opportunistic Infections, 2010.
• Paper # 775. C van Halsema, V Chihota, J Lewis, E Russell, K Fielding, G Churchyard, and A Grant. The Effect of Antiretroviral Therapy on Tuberculosis Sputum Smear Status in HIV-Infected Individuals in South Africa. 17^th Conference on Retroviruses and Opportunistic Infections, 2010
• S Charalambous, Telisinghe L, Puso T, Lethoba J, Hippner P, Grant A, Churchyard G. Poverty and TB-HIV in prisons and community response: The case of South Africa. 40^th World Conference on Lung Health. Int J Tuberc and Lung Dis. 2009;12:Supplement 1, S4
• EL Corbett, T Bandason, T Duong, E Dauya, B Makamure, GJ Churchyard, BG Williams, SS Munyati, AE Butterworth, PR Mason, S Mungofa, RJ Hayes. Impact of periodic case-finding for symptomatic smear-positive disease on community control of prevalent infectious tuberculosis: a community randomised trial of two delivery strategies in Harare, Zimbabwe (DETECTB: ISRCTN84352452). 40^th World Conference on Lung Health. Late Breaker abstract.
• L Telisinghe et al. Preventing TB in the workplace: the health care workers perspective, SA TB conference, 2010
• A Tongman et al. Feasibility, acceptability and yield of  tuberculosis  household contact  tracing  within Rustenburg sub-district municipality. The “Ribolola” Project. (Oral presentation). SA TB conference,2010

 

Recent THRio Publications:

 

Published 

1. Guerra RL, Conde MB, Efron A, Loredo C, Bastos G, Chaisson RE, Golub JE. Point-ofcare Arkansas method for measuring adherence to treatment with isoniazid. Respir Med. 2010 May;104(5):754-7.

 

Submitted

Antonio G Pacheco, Valeria Saraceni, Suely H Tuboi, Lilian M Lauria, Lawrence H Moulton, José Cláudio Faulhaber, Bonnie King, Jonathan E Golub, Betina Durovni, Solange Cavalcante, Lee H Harrison, Richard E Chaisson, Mauro Schechter. Estimating the extent of underreporting of mortality among HIV infected individuals in Rio de Janeiro, Brazil. AIDS Research and Human Retroviruses.

 

Abstracts

• J.E. Golub, V. Saraceni, S. Cohn, A.G. Pacheco, L.H. Moulton, S.C. Cavalcante, A. Efron, R.E. Chaisson, B. Durovni. Value of the tuberculin skin testing for isoniazid preventive therapy for HIV-infected patients. Accepted: IAS 2010, Vienna.
• Valeria Saraceni, Antonio Guilherme Pacheco, Jonathan E. Golub, Silvia Cohn, Solange C. Cavalcante, Lawrence Moulton, Betina Durovni, Richard E. Chaisson . Timing of HAART initiation for HIV-tuberculosis co-infected patients in the THRio cohort, Rio de Janeiro, Brazil. Poster Presented: 14th International Workshop on HIV Obervational Databases ,Barcelona, Spain, March 2010.
• V. Saraceni, A.G.F. Pacheco, S. Cohn, R.T. Brito, L.H. Moulton, S.C. Cavalcante, R.E. Chaisson, B. Durovni, J.E. Golub. Invasive cervical cancer among HIV-infected women in the THRio HIV cohort, Rio de Janeiro, Brazil. Poster-Accepted: IAS 2010, Vienna.
• Valeria Saraceni, Cecilia Carmen de Araujo Nicolai, Maristela Cardozo Caridade, Solange César Cavalcante, Betina Durovni, Richard E. Chaisson, Rosanna Iozzi da Silva, Jonathan E. Golub. Tuberculosis and multiple causes of death in Rio de Janeiro, Brazil: Underestimation of TB burden. Submitted: 41st Union World Conference on Lung Health, 2010.
• Vellozo, Vitória; Israel, Giselle; Santos-Filho, Ezio; Durovni, Betina; Cavalcante, Solange.Delivering IPT for HIV/AIDS Patients in a Larger Scale in Brazil: Fostering Partnerships. Submitted: 41st Union World Conference on Lung Health, 2010.
• Vellozo, Vitória; Israel, Giselle; Lauria, Lilian; Cavalcante, Solange; De Luca, Andrea Local Government and Civil Society: a partnership to prevent Tuberculosis in impoverished communities. Poster, Presented: 9th Brazilian Congress on Public Health, 2009.

 

Recent ZAMSTAR Publications:

 

Published

1. Annual risk of tuberculous infection using different methods in communities with a high prevalence of TB and HIV in Zambia and South Africa. Shanaube K, Sismanidis C, Ayles H, Beyers N, Schaap A, Lawrence KA, Barker A, Godfrey-Faussett P. PLoS One 2009;4(11):e7749.

 

In Press

• Tuberculosis among community-based healthcare researchers. Mareli M. Claassens, Charalambos Sismanidis, Katherine-Anne Lawrence, Peter Godfrey-Faussett, Helen Ayles, Donald A. Enarson, Nulda Beyers Int J Tuberc Lung Dis. In Press 2010.

 

Submitted

• Accuracy and completeness of recording of bacteriologically confirmed tuberculosis in two high incidence South African communities. R. Dunbar, K. Lawrence, S. Verver, D.A. Enarson, C. Lombard, J. Hargrove, J. Caldwell, N. Beyers, J. M. Barnes. Int J Tuberc Lung Dis. under revision, anticipated 2010.

 

ZAMSTAR-Related

• Tuberculosis infection in Zambia: the association with relative wealth. Boccia D, Hargreaves J, Ayles H, Fielding K, Simwinga M, Godfrey-Faussett P. Am J Trop Med Hyg. 2009;80(6):1004-11.
• The fourth I: scaling up implementation of collaborative TB-HIV activities to protect vulnerable mothers and infants. Gie RP, Beyers N. Int J Tuberc Lung Dis. 2009;13(12):1443.
• Screening and preventive therapy for tuberculosis. Marais BJ, Ayles H, Graham SM, Godfrey-Faussett P. Clin Chest Med. 2009;30(4):827-46.

 

AIDS Supplement, 2010:

 

“Implementation of wide-scale isoniazid preventive therapy to control HIV-related tuberculosis”

 

Guest Editors: Alison Grant, Haileyesus Getahun and Richard E. Chaisson

Background: The Consortium to Effectively Respond to the AIDS-TB Epidemic (CREATE) has been conducting large community-based trials on isoniazid preventive therapy (IPT) and intensified tuberculosis case finding in high burden settings in Brazil, South Africa and Zambia. CREATE has generated substantial data and experiences that will be crucial to inform the development of global policies for rollout of IPT. The WHO has recently revised its evidence-based policies on IPT for people living with HIV, and new guidelines are expected to be finalized in the first quarter of 2010. The experience of CREATE projects in implementing IPT will be of great benefit to HIV care programs in high burden settings as they begin to adopt IPT. Publication of the CREATE research and implementation experiences with IPT will assist in the implementation of this global policy development process.

 

Articles

1.  An overview of the CREATE community randomized studies. A description of the CREATE studies. (Lois Eldred, Richard Chaisson, Peter Godfrey-Faussett, Gavin Churchyard and Betina Durovni) Eldred LJ, Churchyard GJ, Durovni B, Godfrey-Faussett P, Chaisson RE. Introduction to the Isoniazid Preventive Therapy for HIV-Infected People Supplement.

 

2. Symptom and chest radiographic screening for infectious tuberculosis prior to starting isoniazid preventive therapy: yield and risk factors for prevalent tuberculosis. Churchyard GJ, Lewis JJ, Grant AD, Chihota VN, Fielding KL. This paper will describe experience using symptoms and CXR to screen for active TB prior to IPT among over 27,000 individuals enrolled in the Thibela TB Research project. The paper will describe the prevalence of active TB at screening plus risk factors for active TB.

 

3. Risk factors for active tuberculosis missed at screening prior to starting isoniazid preventive therapy. factors for being a "missed case" of active TB at screening prior to IPT among over 27,000 individuals screened for TB as part of Thibela TB Research Project.

 

4. Adverse events with isoniazid preventive therapy: experience from a large trial in South Africa. Grant AD, Fielding KL, Mngadi K, Churchyard GJ. This paper will describe the prevalence and risk factors for adverse events among people taking IPT in the Thibela TB Research Project.

 

5. Tolerability and minor adverse effects during isoniazid preventive therapy among participants of a cluster randomised controlled trial in South Africa. Mngadi K, van Halsema C, Luttig M, Fielding KL, Churchyard GJ, Grant AD. This paper will provide the detailed description of more minor side effects among people taking IPT in Thibela TB Research project and discusses their implication for scaling up IPT as a public health intervention.

6. “Team up against TB”: promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy among gold miners in South Africa. Grant AD, Coetzee L, Fielding KL, Lewis JJ, Clark D, Churchyard GJ. This paper will describe the activities undertaken to educate  communities and enhance their involvement in the implementation of the research project. It will also discuss the implication of community mobilization in the scale up of IPT.

 

7. Barriers to implementation of isoniazid preventive therapy in HIV clinics: a qualitative study in South Africa. Barriers to implementation of isoniazid preventive therapy in HIV clinics: a qualitative study in South Africa. Lester R, Hamilton R, Charalambous S, Dwadwa T, Chandler C, Churchyard GJ, Grant AD. This paper will present a qualitative study using in-depth interviews with health care providers in an ART programme in South Africa to investigate why IPT is not implemented, despite policy and guidelines recommending it. The paper will describe the many misconceptions among medical staff and practical obstacles in TB screening and suggest solutions.

 

8. The implementation of IPT in HIV clinics: the experience from Brazil: This paper will describe the implementation of IPT in THRio Research Project sites in Brazil and present the lessons learned. This paper will particularly discusses and present data on the use of skin test for IPT and the utility of secondary IPT prophylaxis. (Lead authors: Betina Durovni and Richard Chaisson)

 

9. Provision of IPT to household contacts of TB patients in Zambia and South Africa. This paper will describe the results of a program to treat household contacts with and without HIV infection after exposure to an infectious TB case. (Lead authors: Helen Ayles, Nulda Beyers and Peter Godfrey-Faussett)

 

10. Why have IPT trials among people with HIV infection not demonstrated an effect on mortality? Grant AD, Fielding KL, Charalambous S, Chaisson RE, Churchyard GJ.

 

11. The global implementation of IPT 2002-2010: challenges for scale-up: This paper will present a review of global data on the implementation of IPT globally that was collected through the WHO system and discusses factors that are essential for scale up. It will also discuss the challenges and barriers identified for the global scale-up including monitoring and evaluation issues. (Lead authors: Haileyesus. Getahun, Christian Gunneberg, Reuben Granich, and Paul Nunn)

 

12. Association of isoniazid preventive therapy with lower early mortality in individuals on antiretroviral therapy in a workplace programme in South Africa. Charalambous S, Grant AD, Innes C Hoffmann C J, Dowdeswell R, Pienaar J, Fielding KL, Churchyard GJ.

 

13. Tolerability and minor adverse effects during isoniazid preventive therapy among participants of a cluster randomised controlled trial in South Africa. Mngadi K, van Halsema C, Luttig M, Fielding KL, Churchyard GJ, Grant AD.