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CDC Region 10, Chiang Mai
Dr. Chawalit Natpratan
Dr. Tasana Leusaree
Sumalee Ammarinsangpen
Anongporn Prapanwong

AIDS Division
Lisa Guntamala

Mahidol University, School of Public Health
Dr. Sukhonta Kongsin

JICA AIDS II
Dr. Masami Fujita

WHO Thailand
Dr. Ying-Ru Lo
Laksami Suebsaeng

2. Background

3. Assessment

4. Discussion

5. Recommendations

References

Annex

1. IPT assessment tool for mail survey
2. Assessment tool to identify critical issues for the implementation of IPT services for PWHA
3. IPT assessment tool for failure case analysis
4. Results of site visits for IPT assessment
5. Results of IPT failure case analysis
6. Schedule of site visits

Tuberculosis ( TB ) is one of the leading causes of HIV-related morbidity and mortality, and HIV infection is largely responsible for the increase of new TB cases in Thailand. The efficacy of isoniazid therapy to prevent the progression of latent TB infection to active disease in HIV-infected persons is well established. Yet published data on this intervention integrated into routine health care services are limited.

Nine to twelve months Isoniazid Preventive Therapy ( IPT ) for HIV-infected persons was initiated years before Directly Observed Therapy, Short-course ( DOTS ) was adopted in the upper north of Thailand where HIV seropositive rate in new TB patients was the highest in the country. The preventive therapy ( PT ) programme was a local response of health care providers to the increase of HIV and TB dual infections and to the recommendations on the efficacy of PT drawn from feasibility studies. The assessment showed that PT can be integrated into routine health care setting but that investments have to be made prior to the implementation.

Key issues for the implementation of PT were identified during this assessment. Better results for the completion of PT were achieved:

1. when PT was offered as a component of comprehensive HIV/AIDS care package for improving compliance,
2. when PT was offered to HIV-infected persons at DCC with regular activities for PWHA,
3. when the service was managed or well-linked to the AIDS unit, and
4. when repeated counselling on PT before and during the therapy was performed.

The following additional recommendations would greatly benefit to the programme:

1. to develop a close collaboration between TB and AIDS programmes by jointly planning strategies for prevention and treatment of TB in PWHA
2. to develop preventive therapy guidelines,
3. to train health care workers prior to the implementation, especially for pre-treatment screening for active TB, and
4. to perform monitoring and supervision by provincial and regional level,

Thailand is implementing a large scale programme on Prevention of Mother to Child Transmission ( PMTCT ) which includes care for HIV-infected mothers and children. The recruitment of mothers for PT of latent TB infection could be an entry point to HIV care.

The diversion of resources from TB clinic could be minimized when integrating preventive therapy into a care package for HIV-infected individuals under the responsibility of AIDS unit.

The lessons learned from the upper north of Thailand on PT provide valuable information to health policy planners, programme implementers and health care providers for the implementation of PT of latent TB infection for HIV-infected individuals.

2. Background
2.1 Preventive therapy of latent TB infection in adult HIV-infected persons

• " those living in population with high prevalence of TB infection ( estimated to be > 30% );
• health care workers;
• household contacts of TB patients;
• prisoners;
• miners;
• other selected groups at high risk of acquisition or transmission of TB ".

2.2 HIV and TB dual infections in Thailand

3.1 Goal and objectives

The purpose of the assessment was to identify key issues for the implementation of IPT for HIV-infected individuals integrated into routine health care services.

The objectives of the assessment were to:

• Describe the situation of the implementation of IPT for HIV-infected individuals integrated into health care services in the upper north of Thailand
• Analyze reasons for success and identify key constraints
• Make recommendations for the design of a strategy to improve existing IPT services and the development of guidelines on preventive therapy

3.2 Methodology

For the communicable disease control , Thailand is divided into 12 regions. The Upper northern part or region 10 comprises of 6 provinces : Chiang-Mai, Chiang-Rai, Lampang, Lamphun, Payao and Mae-Hongson provinces with the total population around four millions and the total of 71 hospitals under PHO of ministry of public health. The region 10 showed the highest HIV seropositive rate in new TB patients in the country and was proposed for the preventive therapy assessment.

The framework for the assessment and the tools were developed by a working group consisting of representatives from CDC region 10 , AIDS Division, Mahidol University ( Faculty of Public Health ), JICA AIDS II , and WHO ( Thailand ).

Following sources obtaining quantitative and qualitative data were used:

1. A mail survey was conducted in 71 government hospitals in region 10 in October 1999 ( Annex I ). The questionnaires were sent to the hospital directors, who would assign the person in charge of PT to respond to the questionnaire. The non responding hospitals were called by telephone to obtain information on the existence of PT services.
2. Six IPT providing hospitals were selected for site visits as following :

The six study sites were visited in December 1999 during a period of 4 days for data collection. Retrospective data collected and documented by the hospital staff in logbooks containing information on outcome of PT and TB treatment as well as documents and publications presented during site visits were collected. Semi-structured interviews with hospital directors, HIV counsellors, nurses and physicians from the IPT managing units and TB clinic were conducted ( Annex II ). Three study sites reporting IPT failure cases were revisited in May 2000. Cases with active TB during IPT, after IPT and in defaulters were analyzed based on OPD cards and CXR films ( Annex III ).

3.3 Results

• Pre-test counselling
• Voluntary HIV testing
• Post-test counselling
• For HIV-positive persons

• CXR screening, sputum smear for AFB
• Body mass index measurement
• Symptomatic/asymptomatic HIV

• IPT counselling
• Enrollment
• Written consent
• History taking and physical examination by using IPT screening form
• Drug regimen : 300 mg H OD + 10 mg vitamin B6 OD for 9 months
• CXR at 9, 12, 18, 24 and 36 months after starting of IPT
• Default tracing by letter, telephone and home visit

During 1995 - 1997 PWH clients were registered for IPT and collected monthly drug supply at TB clinic. Then the drug supply was collected monthly at the hospital based DCC. IPT was offered to all PWH registered at DCC. Registration for IPT was offered twice monthly. Registration and follow-up logbooks were maintained by TB clinic staff. Clients from other sources such as persons attending the anonymous clinic and patients who consulted OPD for other illnesses but found to be HIV-infected were allowed to register at TB clinic. Examinations as CXR, SS, CBC, and drugs for IPT were provided without charge for registered DCC members. Clients from other sources were charged for CXR and laboratory evaluation. In the first two years the pre-treatment screening was performed according to the recommendations of TB center region10 feasibility study. In 1998 symptomatic patients with low grade fever, oral thrush, weight loss and history of OIs were also offered IPT.

Daily DCC services, regular monthly DCC meetings of the PWHA network and the distribution of social welfare were ensuring that clients returned regularly to the hospital. Clients receiving IPT were motivated to continue treatment. Defaulter tracing system was established using letter, home visit by registered DCC members and DCC staff. There was no follow up system after IPT completion.

PCP prophylaxis was offered to all DCC clients with oral thrush and history of/current AIDS defining illnesses or documented CD4<200 cells/m L or total lymphocytes<1.2 x 10⁹/L. The outcome data was not collected by the assessment team.

Figure 7 Management of IPT and its related services in hospital C

• The 1^st patient developed PTB on the 7^th day after the initiation of IPT. No CXR and SS were performed during pre-treatment screening. Upon diagnosis of tuberculosis, CXR showed right upper lobe infiltration but SS was negative. The patient was classified as treatment category 1 ( CAT1 ) and died during TB treatment.
• The 2^nd patient developed smear positive PTB during the 4^th month of IPT. The patient had prior history of herpes zoster. Pre-treatment screening did not include CXR but SS was negative. Upon diagnosis of tuberculosis, CXR showed left upper lobe infiltration and SS was positive. The CAT1 treatment failed.
• The 3^rd patient developed smear negative PTB during the 5^th month of IPT. Pre-treatment screening with CXR and SS were negative. The patient completed TB treatment but died one month later due to PCP.
• The 4^th patient developed EPTB with cervical lymphnode enlargement just on the 3^rd day of IPT. CXR was normal and SS was not done. There was no data of physical examination in the OPD card. The patient completed CAT1 treatment.
• Retrospective study of CXR film of the 5^th patient revealed an abnormality ( mild infiltration in left upper lung ). SS was negative. CXR at the time of TB diagnosis showed mild left upper lung infiltration with small cavity. The patient developed smear negative PTB after one month IPT and died one month after initiation of CAT1 T treatment.

The result of IPT failure case analysis demonstrated that pre-treatment screening would need improvement. Physical examination to exclude EPTB was not properly performed and CXR films were either not done or misinterpreted. The death of TB/HIV patients due to PCP could have been delayed through the provision of primary prophylaxis of PCP.

TB Treatment

DOTS was initiated in 1997 and TB treatment outcome was improved during the first two years, cure rate increased from 26% to 54% and defaulter rate decreased from 33% to 14% as shown in table 8. High death rates were likely due to HIV co-infection. All new TB cases were offered VCT.

Issues

Issues discussed in the hospital were low completion rate, high defaulter rate and high death rate of IPT outcome. Then the service was adjusted by shifting the drug collection to DCC in order to achieve a better follow-up of clients returning regularly to the hospital in 1997. The improved outcome of IPT resulted in shifting the responsibility for IPT registration and follow-up system to DCC under AIDS unit in 2000. High death rates in 1998 was most likely due to inclusion of clients with symptomatic HIV. Failure cases during IPT were due to improper pre-treatment screening like missing physical examination, missing CXR or misinterpretation of CXR. Pre-treatment screening would need to be revised. Monitoring and follow-up system after IPT completion could provide information on the effectiveness of IPT. IPT programme created a good linkage between HIV counselling, TB clinic, and AIDS unit. Hospital staff stated the need for national policy guidance as well as technical guidance through training and supervision for successful integration of IPT into routine services. IPT was considered as beneficial to prevent TB in PWH.

3.3.2.6. District Hospital D

Outcome of IPT and management of the service

During 1996 – 1998 : 8,954 clients were HIV tested and 1,623 ( 18% ) were tested HIV-positive. 608 HIV-infected persons were enrolled to IPT. Data of IPT enrollment and outcome are shown in table 9 and figure 8.

The managing unit for TB and IPT services was sanitation section with four permanent staff. Clients could register daily for IPT and collected one month’s drug supply while drug collection was offered once weekly at TB clinic. AIDS committee, consisting of alternating staff from different hospital sections provided pre and post test counselling at the counselling unit and twice monthly services at the DCC. There was no established collaboration between TB clinic and AIDS committee.

During 1995 - 1998 PWH from anonymous clinic and DCC were offered IPT. As the outcome of IPT was considered as insufficient then TB clinic decided to offer IPT to clients from other sources who were asymptomatic HIV and more likely to comply. Since mid 1998 HIV-positive mothers from PMTCT programme returning to WBC one month after delivery were offered IPT. This change did not yet have an impact on the outcome.

Pre-treatment screening was performed according to the recommendations of TB center region10. Nine months self administered H and vitamin B6 were prescribed monthly at TB clinic. According to the interviewed staff , symptomatic HIV and clients with history of OIs were also offered IPT. CXR ( 80 Baht ) and SS ( 30 Baht ) had to be paid by clients except or low income card holders. Drugs were provided free of charge. There was no follow up system after IPT completion. There was no defaulter tracing system in the hospital but it was delegated to health centers.

PCP primary prophylaxis was not offered.

Figure 9 Management of IPT and it’s related services in hospital D

IPT failure case analysis : Hospital D

OPD cards and CXR films of 9 IPT clients developing TB were analyzed ( Annex V ). The result showed 3 cases turned out to be defaulters, 1 was a failure case after IPT completion, 2 TB patients were registered by mistake in IPT logbook, and 3 patients developed active TB during IPT.

The three cases developing TB during IPT were described as following;

• The 1^st patient developed active TB during the second week of IPT. History taking, physical examination, CXR and SS at the time of pre-treatment screening were not done.
• The 2^nd patient developed smear negative PTB during the 5^th month of IPT. CXR at one month prior to the initiation of IPT revealed a left upper lung infiltration and SS was not done. After completion of CAT1 TB treatment the patient was mistakenly registered for IPT and received H for 1 month.
• The 3^rd patient developed smear positive PTB one month after initiation of IPT. Retrospective study of CXR revealed enlarged paratracheal lymphnodes. The patient completed TB treatment.

These data indicated inadequate pre-treatment screening. There was error in registration of IPT and TB treatment , since both services were managed by TB clinic.

TB Treatment

DOTS programme started in 1996 and soon became a priority in the hospital. Still cure rate and defaulter rates were not achieved NTP targets ( Table 10 ). All new TB cases were offered VCT. HIV-positive TB patients were not allowed to attend DCC activities until completion of treatment.

Issues

Pre-treatment screening, registration and follow-up were not meeting the requirements of the high number of clients registered for IPT every year. Limited number of staff managing more than 200 IPT clients per year , and around 60 TB patients per year were leading to poor outcomes of both services. Provision of PT caused high workload to TB clinic. Issues related to PT of latent TB discussed among HCW were the low completion rate and high death rate during IPT. It was considered as a disadvantage that no medical doctor was permanently assigned to TB clinic for consultation. TB clinic decided to follow the suggestion of TB center region 10 to target HIV-positive mothers from ANC unit. This would reduce the number of clients enrolled. The exclusion of symptomatic HIV would reduce high death rate during IPT. Scarce resources would be used more effectively. Hospital staff stated a lack of national policy guideline and lack of technical guidance through training and supervision.

3.3.2.7. District Hospital E

Outcome of IPT and management of the service

In 1998, 545 clients were HIV tested and 144 ( 26% ) were tested HIV-positive ( Table 3 ). 82 were enrolled to IPT. Data of IPT enrollment and outcome are shown in table 11 and figure 10.

Table 11 Number of HIV-positive persons enrolled for IPT and outcome data of hospital E by year

 

Figure 10 Outcome of IPT for PWHA in hospital E

Sanitation section was responsible for VCT, TB clinic and IPT ( Figure 11 ). AIDS unit was not established. HIV-positive clients from VCT were offered IPT during post-test counselling.

IPT programme recruited PWH from VCT. History taking and physical examination for pre-treatment screening were performed but CXR ( 150 Baht ) and SS ( 30 Baht ) were not done routinely and had to be paid by clients. Asymptomatic HIV Clients were registered for IPT and collected monthly drug supply for free of charge. 9-12 months H and vitamin B6 were prescribed with self administtration. Defaulter tracing system was established and defaulters were traced by counsellor/AIDS volunteers. There was no follow-up system after IPT completion.

PCP prophylaxis was not offered.

Figure 11 Management of IPT and its related services in hospital E

 

TB Treatment

DOTS was initiated in 1998. TB cases with high risk behavior or young age group were offered VCT. Outcome of TB treatment in 1998 and 1999 showed improvement due to active commitment at district level as well as small number of TB cases. ( Table 12 ). In 1997 most of DOTS watchers were family members and shift to HCW in 1999.

Table 12 Treatment outcome in new smear positive PTB in hospital E

 

Issues

Overburdened services with sanitation section managing VCT, IPT and TB/DOTS may have contributed to low completion rate and high defaulter rate of IPT. IPT seemed to be relatively low priority among these services. There was no feedback on the benefit of providing IPT and IPT was considered as additional workload. Adverse events were not clearly defined and resulted in a high proportion of clients stopping IPT. The interviewed staff mentioned lack of national policy guidelines and technical guidance on IPT through training and supervision as well as lack of financial resources as major issues. AIDS unit with permanently assigned staff would improve comprehensive care and support for PWHA.

3.3.2.8. District Hospital F

Outcome of IPT and management of the service

Nine to 12 months duration of IPT was offered since 1995. However data from 1995 to 1996 were not available. During 1997 - 1998 a total of 1,901 clients were HIV tested, and 178 ( 9% ) tested HIV-positive and 168 clients were enrolled to IPT. Data of IPT enrollment and outcome are shown in table 13 and figure 12.

Table 13 Number of HIV-positive persons enrolled for IPT and outcome data of hospital F by year

Figure 12 Outcome of IPT for PWH in hospital F

 

Sanitation section was responsible for VCT, DCC, IPT and TB clinic. One nurse was in charge for HIV counselling, IPT and TB treatment. Clients from following resources were recruited for IPT: HIV-positive persons from VCT and registered members of the hospital based PWHA group. Clients could register daily for IPT at sanitation section. Drugs were collected once monthly at DCC. Pre-treatment screening was to follow the recommendations of TB center region 10. This was not always possible practiced due to high workload of the nurse. Asymptomatic and mildly symptomatic HIV persons were enrolled. Clients were not charged for drugs and TB screening. Defaulters were traced by DCC members, hospital staff and AIDS volunteers visiting clients’ homes. Log books were managed by staff of sanitation section. Clients were followed up for 4 years after IPT completion with CXR annually. These data were not documented in a log book but in OPD card.

 

PCP primary prophylaxis was not offered.

IPT failure case analysis : Hospital F

OPD cards and CXR films of 5 IPT clients developing TB were analyzed ( Annex V ). The result showed 1 case of defaulter, 3 cases developed TB after IPT completion and 1 case failure during IPT.

The case developing TB during IPT was described as following;

• The patient was diagnosed as smear negative PTB just 3 weeks after starting IPT. CXR at pretreatment screening and at the time of TB diagnosis of this patient were reviewed; perihilar infiltration and bilateral interstitial infiltration were seen respectively. The patient was treated with CAT1 and died 2 months later. Whether this patient had another pulmonary infection instead of TB was never studied.

TB Treatment

TB clinic was initiated DOTS in 1999 . VCT was offered to new TB cases between 15 - 45 years of age. A total of 30 TB patients were treated ; 8 cured, 21 died and 1 patient defaulted.

Issues

PT for latent TB infection in PWH as well as HIV/AIDS care were not priority in this hospital. Resources allocated were scarce. The nurse in charge for HIV/AIDS and TB had too many tasks to fulfill. Prevention and treatment of OIs including DOTS for TB treatment should be priority. If IPT would be continued; additional staff, training, improvement of pre-treatment screening, follow-up and documentation would be required. Supervision and monitoring would provide feedback on the quality of the service .

Though achieving a satisfactory outcome, IPT was not sustainable when implemented as part of a feasibility study in TB clinic of regional hospital A. Nearly 1000 new active TB cases were presenting to TB clinic each year. Major efforts should be made to modify favorably the structure of services by shifting therapy for active TB to health center level as promoted by NTP ( DOTS strategy ). This would reduce the workload of TB clinic.

The assessment at district hospitals showed that better results could be achieved when offering PT for PWH in DCC of AIDS unit. Follow-up of clients seemed to be easier where DCC with regular activities for PWHA and active PWHA groups were established. Adherence was good when repeated counselling before and during PT were conducted.

The poor outcome of both services was observed when offering PT and TB treatment to a large number of patients. Errors during registration and follow-up for PT and TB treatment occurred when both programmes were managed by the same unit. Improvement of cure rate and reduction of defaulter rate for TB treatment should be the priority of TB clinic. A linkage to AIDS unit would ensure long-term follow-up of PWH for HIV-related health assessments and access to other HIV-related prophylactic and curative treatments. The provision of primary prophylaxis for PCP would reduce the mortality in dually infected TB/HIV patients.

IPT recruiting for HIV-positive mothers who had attended ANC and were enrolled in PMTCT, was an approach discussed and recently implemented in the district hospitals. Evidence that targeting this group would improve uptake of PT and adherence remains to be demonstrated.

HCW lacked knowledge on proper screening to exclude active TB. Both, guidelines and training on PT would have contributed to a better management. Inclusion of PWH with advanced immunosuppression have a higher probability to develop active TB, to progress to AIDS or to die during IPT. It is also more difficult to diagnose active TB in this patient group. One study suggested that PT may be less effective in this group ( Mwinga A, et al, 1998 ). Given the limited resources available recruitment of this group should be reconsidered. Supervision, monitoring and evaluation on IPT programme by provincial and regional levels could have provided feedback on the quality of the programme.

The successful prevention of new HIV infections by the National AIDS Programme had a positive impact on the number of new TB cases in region 10 since these numbers seem to be leveling off since 1996 ( WHO, 1999 ). This positive impact could however hardly be attributed at the moment to the implementation of PT and DOTS.

• DOTS is the priority intervention for TB control. Therefore resources should not be diverted from DOTS implementing services for PT of latent TB for PWH. This kind of interference with DOTS could however be minimized if the service is provided under the responsibility of AIDS unit.

• A guideline on the management of preventive therapy should be developed jointly by AIDS programme and TB programme. Training of HCW should be conducted prior to the implementation.

• Thailand is implementing a large scale programme on PMTCT which includes care for HIV-infected mothers and children. The recruitment of mothers for PT of latent TB infection could be an entry point to HIV care. Further research to improve outcome of PT could focus on targeting HIV-positive mothers from the PMTCT programme.

• Improving compliance is a major issue for the effectiveness of PT. One approach would be to integrate PT of latent TB infection into a basic comprehensive care package for PWHA under AIDS unit or well-linked to the services of AIDS unit. PT could be offered in well-functioning DCC, which are networking with PWHA groups and community-based care organizations. Repeated IPT counselling assessing the readiness for PT and repeated counselling during PT should be reinforced.

• Pre-treatment screening to exclude active pulmonary and extra-pulmonary TB needs improvement. Monitoring, supervision and evaluation of PT outcomes should be established.

• In settings where health care services are overburdened with many tasks the capacity of the unit should be assessed and reinforced in terms of staff allocation, management and organizational structure, and prioritization of the interventions.

Akarasewi P, Natpratan C, Prapanwong A, et al. Risk of active TB in HIV-infected persons following 9 months of INH preventive therapy. Unpublished data.

Anglaret X, Chene G, Attia A, et al. Early chemoprophylaxis with trimethoprim-sulfapmethoxazole for HIV-1-infected adults in Abidjan, Cote d ’Ivoire: a randomised trial. Lancet 1999. 353: 1463-1468.

American Thoracic Society. Targeted tuberculin testing and treatment of latent TB infection. Am J Respir Crit Care Med 2000; 161: S221-S247.

Comstock GW, Baum C, Snider DE. Isoniazid prophylaxis among Alaskan Eskimos: a final report of the Bethel isoniazid studies. Am Ref Repir Dis 1984, 119: 827-830.

Gordin FM, Matts JP, Miller C, et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for TB. NEJM 1997; 337: 315-320.

Gordin F, Richard E, Matts JP, et al. Rifampin and pyrazinamide vs isoniazid for prevention of TB in HIV-infected persons. JAMA 2000; 283: 1445-1450.

Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberdulosis in HIV-1 infection. Lancet 1998; 351: 786-792.

Hawken MP, Meme HK, Elliott LC, et al. Isoniazid preventive therapy for TB in HIV-1 infected adults: results of a randomized controlled trial. AIDS 1997; 11: 875-882.

Kassim S, Sassan-Morokko M et al, Two-year follow-up of persons with HIV-1 and HIV-2 associated pulmonary TB treated with short-course chemotherapy in West Africa. AIDS 1995; 9: 1185-91.

Mwinga A, Hosp M, Godfrey-Faussett P, et al. Twice weekly TB preventive therapy in HIV infection in Zambia. AIDS 1998; 12: 2447-2457.

Natpratan C, Akarasewi P, Prapanwong A, et al. Operational feasibility of isoniazid preventive therapy (IPT) among HIV-infected persons in Chiangmai, Thailand. Unpublished data.

Ngamvithayapong J, Uthaivoravit W, Yanai H, et al. Adherence to TB preventive therapy among HIV-infected persons in Chiang Rai, Thailand. AIDS 1997; 11: 107-112.

Pape JW, Jean SS, Ho JL, et al. Effect of isoniazid prophylaxis on incidence of active TB and progression of HIV infection. Lancet 1993; 342: 268-272.

TB Division Thailand. Guidelines for TB counselling for health counsellors. Department of Communicable Disease Control, Ministry of Public Health 1993.

TB Division Thailand. Battle against TB, National TB Programme Thailand. Department of Communicable Disease Control, Ministry of Public Health 1999.

TB Division. TB Treatment. Department of Communicable Disease Control, Ministry of Public Health, Thailand, 1993.

Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to prevent TB in Ugandian adults infected with the human immunodeficiency virus. NEJM 1997; 337: 801-808.

WHO/GTB. Country Review: Thailand 1995. WHO, Geneva (1995) (NPS), WHO/TB/95.192. http://www.who.int/tb/publications/en/.

WHO/GTB. Second Review of the National Tuberculosis Programme in Thailand, July 1999. Department of Communicable Disease Control, Ministry of Public Health Thailand & WHO 1999. HO/CDS/TB/99.273. http://www.who.int/tb/publications/en/.

WHO/UNAIDS 1998. Policy Statement of Preventive Therapy against TB in People Living with HIV, WHO/TB/98. 255, UNAIDS/98.34. Available at http://www.who.int/tb/publications/en/.

WHO/UNAIDS. Preventive therapy against TB in people living with HIV, WER 1999; 74:385-400.

Wiktor SZ, Sassan-Morokro M, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1 –infected patients with TB in Abidjan, Cote d’Ivoire: a randomised controlled trial. Lancet 1999; 353: 1469-1475.

Zumla A, Squire B et al. The TB pandemic: implications for health in the tropics, Transactions of the Royal Society of Tropical Medicine and Hygiene (1999); 93, 113-117.