The Future Directions for Supporting Tuberculosis Research in Thailand

(MS Word Format)

Summary Report Meeting on
The Future Directions for Supporting Tuberculosis Research in Thailand
On 26 August 2003
09:00am - 04:00pm
At Century Park Hotel, Bangkok

Welcome address:
Dr. Somsak Chunharas, the T-2 Director, addressed to participants at the meeting on the rationale and status of the T-2 Programme which will finish in December, 2003. He also explained the main purpose of the meeting that all the experts from the various fields relating to Tuberculosis were invited for these discussion forum in order to generate the significant suggestions and opinions. All of the results from their discussions will be gathered and recorded to be the references guiding to the research direction on Tuberculosis in Thailand in the future.

I. Review of TB Situation, Epidemiology, Clinical management,
Prevention and Control
Presenter: Dr. Paskorn Akarasewi

Dr. Akarasewi informed those at the meeting of the current status of Tuberculosis. It is a globally re-emerging disease and one of the most common opportunistic infections in existence. When the high-burden countries worldwide are ranked, Thailand is the 22nd in which the first 22 high burden countries share almost 80% of the global burden. The trends of drug resistance especially in the country boarder areas, Criteria for Composite TB Risk Index were mentioned. There was also a review of the current knowledge of TB researches relating to transmission, exposure, prevention and control. Last of all, the interesting researches that should be carried out in Thailand were clarified.

Important points for TB researchers in Thailand from Dr. Akarasewi;

Summary of the comments of the participants:

II. Current status of Anti-TB Drug Development in Thailand
Presenter : Associate Professor Prasit Palittapongarnpim

Dr. Palittapongarnpim briefed those at the meeting on the basic knowledge of the new TB drug, Linezolid. Some of the problems regarding to the developing new Anti-TB drugs were identified including the pharmaceutical part and the governmental part. These difficulties also include the existence of multi drug resistance tuberculosis (MDR-TB), and the fact that there are no reserve TB drugs and there is little incentive for big pharmaceutical companies to develop the new drugs. The US NIH currently provides in vitro, intramacrophage and in vivo screening. However, there has still been no animal testing research sent though this pipe line. NGOs, i.e., Grand Challenges in Global Health and the Global alliance for anti-TB development focus primarily on clinical trials. For research study in Thailand, BIOTEC has been focusing on the Target and lead discoveries, which are the early steps of the pharmaceutical R&D process. Therefore, it is necessary to look for someone who can further develop those lead discoveries and suport them until their final steps.

There was a brief summary of the pharmaceutical R&D process. The Target Discovery, Lead Discovery, Screening method development, Drug candidate searching and developing which were related to the new TB drug development were also presented. He mentioned about the drug target identification especially M. tuberculosis genome including M. tuberculosis H37Rv genome. Dr. Palittapongarnpim also informed the audiences that those steps which have not yet been performed in Thailand include Putative target identification, Proteomics, Interactomics, and Target-based screening formulation. For Lead Discovery, except animal testing, the infrastructure is already set for many institutes. Also, Anti-TB screening test development and Drug candidate searching / development has been done.

Comments
Even though Thai scientists are highly efficient, they are afraid that a Drug discovery is still far off. A very high budget will be necessary for the required funding.

A Word from the T-2 director
The T-2 director emphasized that in order to chief tangible output, it is necessary to have researchers with high research effort focusing their work on selected disease group. He would like all participants to join in the discussion of the topic "What is the research title that should be done next". Can Drug discovery be the focal point of researchers? And last of all, it would be great if the results gathered from the individual research projects can all be combined to complete the big picture, just like the many pieces of a jigsaw puzzle.

III. Diagnosis of TB and Drug resistance
Presenter: Assoc. Prof. Angkana Chaiprasert

Dr. Chaiprasert briefed those at the meeting on the various methods of TB diagnosis that have been used in Thailand from the past to the present. She lectured on the topics of microscopic examination, culture, and identification. She explained that the most effective method of identification is the multiplex PCR and PCR/REA (hsp65, rpoB. 16S-23S spacer) technique. This method can distinguish Mycobacterium tuberculosis from other Mycobacterium. Immunochromatography, which was developed in Japan, is another method that can be used to identify Mycobacterium tuberculosis. Many commercial kits have also been developed recently, so there are now many choices available.
Dr. Chaiprasert explained how the drug susceptibility test (DST) has many pit falls. All national and regional specialists should service this test. For this test to be useful, strict quality control and accuracy are essential. Agar/LJ and MGIT 960 were mentioned. She also said that the goal of diagnosis research should be to decrease the cost and improve the accuracy of testing. Molecular amplification for detection was explained. The in-house PCR (IS6110, 16S-rDNA, MPB64. RpoB, hsp65) technique is usually used in the laboratory in Thailand. Microarray technology is currently developing. This method can show identification of etiologic agents and drug sensitivity profiles. Dr. Chaiprasert emphasized that the following are important for molecular technique :

1. Every method should be evaluated before being put into service.
2. Each step needs high quality control and a high degree of accuracy.
3. When considering a diagnosis, doctors should not interpret the results from the lab without first comparing those results to the clinic prognosis of the patients.
4. A negative test result does not prove that the patients do not have Tuberculosis.

Comments

1. The cost - effectiveness of each laboratory testing nationwide should be evaluated.
2. The test that can report viable bacilli is very important for treatment. The molecular technique that starts from amplified RNA can solve this problem.

Group Discussions

All the participants were organized into three separate groups in order to address the status of each field area in Thailand, introduce the research teams and discuss any other suggestions for a funding agency. The following fields of TB research were discussed and will be documented in order to extend research progress:

1 Drug development and Molecular research
2 Epidemiology, prevention and social science
3 Diagnostic and Clinical research

Summary of the discussions from each group

1. Drug development and Molecular research

I. Identify drug targets
- In silico - Essential genes
- Experiment - Highly express genes in an intracellular environment

II. Drug screening
- Natural compounds - High throughput screening?????
- Synthesis compounds - High throughput screening?????

Pathogenesis
- Virulent genes
- Drug resistance mechanisms

Research groups
- BIOTEC + Mahidol University : Drug Development
- KKU
- Chulalongkorn University Pathogenesis

Suggestions
- Mentor
- Training grants
- TB database

2. Epidemiology, prevention and social science

Activities
- National prevalence survey (disease, infection if affordable)
- Epidemiology & intervention for MDR - TB
- Intervention to accept DOT
- Survey & intervention to improve drug supply system
- Intervention to reduce the burden of TB in relation to HIV and
- Cost-effectiveness evaluation of various DOTs procedures
- Set up for checking drug ingestion

Research issues
- Nosocomial TB transmission
- How to involve steakholders in the TB control program

Research group
- Universities
- RIT and TB-HIV research foundation

Suggestions
- Priority should be given to operational research.
- A unit responsible for maintaining research information in Thailand should be established.

3. Diagnostic and Clinical research

Research issues
I Extrapulmonary TB
- PCR
- Serology
- Culture
- Develop new techniques
II Smear negative pulmonary TB
- Culture
- PCR
- Serology - Antigen
III. Identification
- combine PCR of each species
- Drug susceptibility testing
- Compare Cost effectiveness of conventional and automate method
- Essential in high risk group

IV Follow up treatment: viability
- RT-PCR
- Rif fast plaque

Suggestion for funding agency
- Public relations
- Provide funding

Interesting Research Questions For TB research in Thailand

Epidemiology, Prevention and Social science
1. Development or modified new BCG vaccination
2. Modeling and forecasting TB situation? (and HIV interrelationships)
3. Systemic approach for Drugs Resistant Case Management
4. New treatment regimens of TB in HIV infected persons in Thailand
5. New treatment regimens of Latent TB infection in PLWHs and impact on TB control
6. Identification alternative intervention with equal or better than DOTS in special settings
7. Development of effective programs for early case detection.
8. Cost-Effectiveness of proactive case detection and case holding
9. Health Policy Analysis: TB and Health Care Reform
10. Nosocomial TB transmission
11. How to involve steakholders in the TB control program

Drug development and Molecular research
1. Development of new anti - TB Drugs
2. Develop Target-based screening formulations
3. Screen of Thai herbal plants for substances with antituberculous activity
4. Drug targets in M. tuberculosis genome
5. Pre-clinical study
6. Clinical trial phase I and II study

Diagnostic and Clinical research
1. Comparison of the cost effectiveness of conventional, molecular and automate methods
2. Applying the more effective drug sensitivity test into the practice
3. Detection of tuberculostearic acid in CSF and other samples
4. Detection of adenosine deaminase (ADA) in PF
5. Detection of antibodies Operational research
6. Determination of latent TB infection other than tuberculin skin test (less priority)

Closing remarks

Dr. Ram Rangsin, on behalf of the T-2 Programme, said that it is important for Thailand to develop such research projects on TB by Thai scientists. The T-2 will finish the program soon. However, it is a normal process of the development of such a program that will change for the better. He also stressed the importance of a strong information database and training suggested by the participants. He concluded by saying that he hopes the network of participants assembled there will stay connected. All of the suggestions and comments from the participants will be used as a reference to develop the TB research programme in Thailand.

Reported by : Ms. Taweeporn Gedarram
Approved by: Dr. Somsak chunharas, Dr. Ram Rangsin