Evidence-informed policy making at country level: lessons learned from the South African Tuberculosis Think Tank.

BACKGROUND: National Tuberculosis Programmes (NTPs) require specialist input to support the development of policy and practice informed by evidence, typically against tight deadlines. OBJECTIVE: To describe lessons learned from establishing a dedicated tuberculosis (TB) think tank to advise the South African NTP on TB policy. INTERVENTION AND EVALUATION METHODS: A national TB think tank was established to advise the NTP in support of evidence-informed policy. Support was provided for activities, including meetings, modelling and regular telephone calls, with a wider network of unpaid expert advisers under an executive committee and working groups. Intervention evaluation used desktop analysis of documentary evidence, interviews and direct observation. RESULTS: The TB Think Tank evolved over time to acquire three key roles: an 'institution', a 'policy dialogue forum' and an 'interface'. Although enthusiasm was high, motivating participation among the NTP and external experts proved challenging. Motivation of working groups was most successful when aligned to a specific need for NTP decision making. Despite challenges, the TB Think Tank contributed to South Africa's first ever TB and human immunodeficiency virus (HIV) investment case, and the decision to create South Africa's first ever ring-fenced grant for TB. The TB Think Tank also assisted the NTP in formulating strategy to accelerate progress towards reaching World Health Organization targets. DISCUSSION: With partners, the TB Think Tank achieved major successes in supporting evidence-informed decision making, and garnered increased funding for TB in South Africa. Identifying ways to increase the involvement of NTP staff and other experts, and keeping the scope of the Think Tank well defined, could facilitate greater impact. Think tank initiatives could be replicated in other settings to support evidence-informed policy making.

Modelling the social and structural determinants of tuberculosis: opportunities and challenges.

INTRODUCTION: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants. OBJECTIVE: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB. METHODS: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting. RESULTS: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socio-economic and nutritional status), and one focused on macro-economic influences. CONCLUSIONS: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes.

How can mathematical models advance tuberculosis control in high HIV prevalence settings?

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

The utility of stool cultures for diagnosing tuberculosis in people living with the human immunodeficiency virus.

BACKGROUND: Delayed diagnosis of tuberculosis (TB) increases mortality. OBJECTIVE: To evaluate whether stool culture improves the diagnosis of TB in people living with the human immunodeficiency virus (PLHIV). DESIGN: We analysed cross-sectional data of TB diagnosis in PLHIV in Cambodia, Thailand and Viet Nam. Logistic regression was used to assess the association between positive stool culture and TB, and to calculate the incremental yield of stool culture. RESULTS: A total of 1693 PLHIV were enrolled with a stool culture result. Of 228 PLHIV with culture-confirmed TB from any site, 101 (44%) had a positive stool culture; of these, 91 (90%) had pulmonary TB (PTB). After adjusting for confounding factors, a positive stool culture was associated with smear-negative (odds ratio [OR] 26, 95% confidence interval [CI] 12-58), moderately smear-positive (OR 60, 95%CI 23-159) and highly smear-positive (OR 179, 95%CI 59-546) PTB compared with no PTB. No statistically significant association existed with extra-pulmonary TB compared with no extra-pulmonary TB (OR 2, 95%CI 1-5). The incremental yield of one stool culture above two sputum cultures (5%, 95%CI 3-8) was comparable to an additional sputum culture (7%, 95%CI 4-11). CONCLUSION: Nearly half of the PLHIV with TB had a positive stool culture that was strongly associated with PTB. Stool cultures may be used to diagnose TB in PLHIV.

The cost of intensified case finding and isoniazid preventive therapy for HIV-infected patients in Battambang, Cambodia.

SETTING: The current study evaluates one of four pilot sites initiated in Cambodia to establish feasible and effective ways to manage patients with human immunodeficiency virus (HIV) infection and tuberculosis (TB). OBJECTIVE: To measure the costs of intensified case finding (ICF) and isoniazid preventive therapy (IPT) services for HIV-infected patients in Battambang Province, Cambodia. DESIGN: We analyzed cost data retrospectively from September 2003 to February 2006 using a microcosting or ingredients-based approach and interviewed clinic personnel to determine the cost of ICF and IPT per person. RESULTS: Adherence to IPT at Battambang IPT clinic was high (86%) relative to other reported studies of IPT among HIV patients in developing countries. The estimated cost per TB case averted through ICF was US$363, while the estimated cost per TB case averted through IPT was US$955. CONCLUSION: Economic evaluations of TB-HIV integrated services are necessary as countries move to establish or scale-up these services. Based upon the estimated effectiveness of ICF and IPT used by other studies examining the provision of integrated HIV-TB services, the cost per TB case prevented by ICF and IPT in Battambang, Cambodia, is less than the reported cost of treating a new smear-positive TB case.

Predictors of smear-negative pulmonary tuberculosis in HIV-infected patients, Battambang, Cambodia.

DESIGN: Retrospective data analysis of human immunodeficiency virus (HIV) infected patients attending an HIV clinic (referral hospital), Cambodia. Chest X-rays (CXRs) were read independently by onsite and offsite physicians. RESULTS: Data on 881 patients were analyzed (smear-negative = 776, smear-positive = 105). Overall, the prevalence of culture-confirmed pulmonary tuberculosis (PTB) was 17% (150/881, smear-negative = 62/150). For those with any positive culture, a smear-negative case was four times more likely to be mycobacteria other than tuberculosis (MOTT) than Mycobacterium tuberculosis (P = 0.001). Median CD4 count was higher in smear-negative than smear-positive PTB patients (92.5 vs. 42, P = 0.24). Age, symptoms (cough >3 weeks or hemoptysis or fever >1 month) (aOR 2.6, P = 0.02) and an abnormal CXR (offsite reading) (aOR 4.9, P < 0.001) were significant predictors of smear-negative PTB. CXR was no longer significant in the model using the onsite reading (aOR 1.6, P = 0.11). The combination of age >or=30 years plus symptoms had a sensitivity of 100% but a positive predictive value (PPV) of 9%. CXR (offsite), as the next diagnostic test, had a sensitivity of 50% and specificity of 83%. The sensitivity of smear microscopy was 59% and its specificity 97%. CONCLUSIONS: While age and symptoms are useful both in screening smear-negative PTB suspects and in predicting smear-negative PTB cases, they have limited PPV. Given the limitations of smear microscopy, culture is required to diagnose smear-negative disease. Where culture is unavailable, CXR is an important adjunct for diagnosis. However, inaccurate CXR interpretation can impact case detection.

Early lessons from the integration of tuberculosis and HIV services in primary care centers in Lusaka, Zambia.

BACKGROUND: Zambia faces overlapping tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics; however, care for co-infected patients often occurs through separate, vertical programs. OBJECTIVE: To establish a program to integrate TB and HIV services in Lusaka primary care centers. METHODS: In collaboration with the Zambian Ministry of Health, TB-HIV integration activities began in December 2005 and were expanded to seven health centers by March 2007. Principal activities included developing staff capacity to manage co-infected patients, implementing HIV testing within TB departments and establishing referral systems between departments. RESULTS: Using a provider-initiated approach, 2053 TB patients were offered HIV testing. Seventy-seven per cent agreed to be tested; 69% of those tested were HIV-infected. Of these, 59% were enrolled in HIV care. The proportion of antiretroviral treatment (ART) program enrollees who were TB-HIV co-infected increased by 38% after program implementation. The median CD4 count among co-infected patients was 161 cells/microl, with 88% eligible for ART. CONCLUSION: Integration of HIV testing and referral services into urban primary care centers identified many co-infected patients and significantly increased the proportion of TB patients among people accessing HIV care. Ongoing challenges include maximizing the number of patients accepting HIV testing and overcoming barriers to enrollment into HIV care.

Pulmonary tuberculosis among patients visiting a voluntary confidential counseling and testing center, Cambodia.

SETTING: Voluntary counseling and confidential testing center (VCCT), Battambang District, Cambodia. OBJECTIVES: To determine newly diagnosed pulmonary tuberculosis (PTB) prevalence and predicting factors, and assess the utility of TB-related symptoms and yield of sputum microscopy and culture. DESIGN: Cross-sectional survey using interview, sputum smears and cultures and human immunodeficiency virus (HIV) testing. RESULTS: Of 496 participants, 29 (5.8%) had culture-confirmed PTB while 19 (65.5%) were acid-fast bacilli (AFB) smear-positive. PTB prevalence was higher (P < 0.001) in HIV-positives (20/124, 16.1%) than in HIV-negatives (9/372, 2.4%). On multivariable analysis, being HIV-positive, underweight (body mass index <18.5 kg/m(2)), rapid weight loss and age > or =35 years were predictors of PTB. Fever (93%) and hemoptysis (86%) had the highest sensitivity and specificity, respectively. The symptom complex of rapid weight loss, fever and hemoptysis detected all PTB cases (sensitivity 100%). Examination of three sputum smears with culture of the first sample detected 95% (19/20) of the HIV-associated PTB cases and 90% (26/29) overall. CONCLUSIONS: TB is common in the VCCT setting, regardless of HIV status. The high prevalence of HIV and PTB among the participants warrants consideration of TB screening for all HIV suspects. Such screening through VCCT is feasible. Adding a single culture test to the evaluation of an initial sputum sample set will substantially increase case detection.

Hospital DOTS linkage in Indonesia: a model for DOTS expansion into government and private hospitals.

BACKGROUND: To accelerate DOTS expansion, the hospital sector and specialized chest clinics must be engaged. OBJECTIVE: To develop a model for public-private partnership through DOTS expansion into public and private hospitals in Indonesia. DESIGN: Model development included gaining commitment from stakeholders, stepwise training of hospital staff, and developing unified networks for case management, patient referral, laboratory quality assurance, supervision and evaluation. RESULTS: The number of notified tuberculosis (TB) cases (all forms and new smear-positive) increased dramatically from baseline. Together, hospitals and chest clinics accounted for a significant proportion of the total cases notified by the province (51% of total TB cases and 56% of new smear-positive cases in 2004). Compared to health centers and chest clinics, hospitals reported lower cure and success rates. Despite the option for referral to health centers, the majority of patients diagnosed in hospitals and chest clinics in 2002-2004 opted to be fully managed by the diagnosing facility. CONCLUSION: The roles and strengths of hospitals differ with regard to health centers, providing a rational basis for linkage of these health service components. In Yogyakarta, linkage became effective only after establishing a stakeholder-based provincial coordinating (DOTS) committee as the recognized interface between the National Tuberculosis Programme and various providers.

Evaluating the strengths and weaknesses of tuberculosis educational activities for prisoners in Honduras.

SETTING: Prisons throughout Honduras. OBJECTIVE: To assess the strengths, weaknesses, and opportunities to improve non-standardized tuberculosis (TB) educational campaign materials utilized in prisons. DESIGN: A qualitative assessment was conducted. Prison staff completed a survey describing development and implementation of educational activities at each prison (n=25). Completed surveys with photographs or copies of educational materials were collected and cataloged. The content, literacy demand, illustrations, learning stimulation, and cultural appropriateness of cataloged items were assessed using an adapted version of the Suitability Assessment of Materials Instrument. Results from this assessment were examined in conjunction with information collected through focus groups conducted with prisoners and interviews with prison staff. RESULTS: Campaign strengths included the development and dissemination of print materials appropriate for individuals with low literacy levels. By actively engaging prisoners in the campaigns, materials often incorporated the language, values, and experiences encountered within prison culture. Content of print materials and presentations focused on correcting misperceptions and facilitating acceptance of TB control activities. Campaign weaknesses included the creation of illustrations that could perpetuate the stigma associated with TB and use of some materials in which the purpose was not apparent. CONCLUSIONS: The campaigns were generally suitable, and the evaluation allowed for their improvement.

Standardizing contact investigation protocols.

SETTING: The State of Alabama Department of Public Health Division of Tuberculosis Control. OBJECTIVE: To standardize contact investigation protocols and implement an intervention to increase TB field worker adherence to the protocols with the goal of promoting efficiency and effectiveness in contact investigations. DESIGN: A process evaluation of existing data collection and management systems and protocols was performed. Standardized protocols and an intervention to increase TB field worker adherence to the protocols were created and pilot tested. These were then implemented and formative evaluation data were collected. RESULTS: The process evaluation revealed considerable variance among field workers with regard to protocols and definitions of variables related to contact investigations. Protocols were standardized and an intervention targeted at TB field workers was developed. The intervention consisted of a training workshop and the development of a computer-based contact investigation module. This was successfully implemented throughout the state. CONCLUSIONS: To perform effective contact investigations and conduct studies to improve the effectiveness of these investigations, TB control programs must pay careful attention to precisely defining variables and concepts related to the contact investigation. Furthermore, protocols must be standardized and resources devoted to training of TB field workers to ensure adherence to protocols.

The risk of MDR-TB and polyresistant tuberculosis among the civilian population of Tomsk city, Siberia, 1999.

SETTING: Tomsk, Siberia, Russian Federation. OBJECTIVE: To evaluate the relationship between TB susceptibility patterns and risk factors among a civilian cohort of new cases in Tomsk city in 1999. DESIGN: Population-based study. The association between MDR-TB or PROMDR-TB, defined as resistance to isoniazid and rifampicin (MDR) or to isoniazid, ethambutol, and streptomycin (rifampicin mono-sensitive), and hypothesized risk factors was determined. Univariable analysis with and without stratification for history of incarceration and stepwise logistic regression modeling were used. RESULTS: Overall, 49.6% of participants were infected with a Mycobacterium tuberculosis strain resistant to at least one prescribed anti-tuberculosis medication. PROMDR-TB and MDR-TB were prevalent in 17.2% and 13.1% of participants, respectively. Logistic regression modeling indicated that good residence (OR 3.1, 95%CI 1.4-6.9), treatment default (OR 4.4, 95%CI 2.1-9.3) and psychological disorder (OR 3.3, 95%CI 1.0-10.9) were associated with PROMDR-TB. Both good residence (OR 2.6, 95%CI 1.1-6.0) and treatment default (OR 5.3, 95%CI 2.4-11.6) were associated with MDR-TB. History of incarceration was not found to be significant. CONCLUSION: Our findings support the hypothesis that drug-resistant disease among the Tomsk city population is not directly linked to history of incarceration, nor is it an extension of drug resistance in prisons. Rather, drug resistance in the civil sector reflects problems specific to the sector itself.

Prevalence of pulmonary tuberculosis among HIV-infected persons in a home care program in Phnom Penh, Cambodia.

SETTING: Phnom Penh, Cambodia. OBJECTIVE: To determine the burden of active pulmonary tuberculosis among an HIV-infected cohort and the proportion of drug-resistant strains, using active case-finding adapted to a home care setting. DESIGN: Cross-sectional study. Measures include the prevalence of culture-confirmed Mycobacterium tuberculosis, utilizing a single spot sputum specimen; the proportion of pulmonary TB, detected and undetected; proportion of cases resistant to isoniazid, rifampicin, ethambutol, streptomycin; and the diagnostic value of symptoms. RESULTS: Of 441 persons surveyed, 41 (9%) had active pulmonary TB by culture; 29 were smear-positive (71%), and only one case was on treatment. The total burden of pulmonary TB was 12% (54/441), with a ratio of undetected to detected cases of 3:1. Primary isoniazid resistance was detected in six new cases (15%); no MDR-TB was identified. Symptoms were not predictive of active pulmonary disease. Mortality was high among those not surveyed (20%) and those found to have TB (49%). CONCLUSIONS: Tuberculosis is epidemic in this HIV-infected population. Active case-finding yielded three times the number of cases already detected and should be considered where resources allow. However, effective passive case detection and improved coordination of TB and HIV care programs are required to address HIV-associated TB morbidity and mortality.

Identification of a contaminating Mycobacterium tuberculosis strain with a transposition of an IS6110 insertion element resulting in an altered spoligotype.

Molecular fingerprinting with the IS6110 insertion sequence is useful for tracking transmission of Mycobacterium tuberculosis within a population or confirming specimen contamination in the laboratory or through instrumentation. Secondary typing with other molecular methods yields additional information as to the relatedness of strains with similar IS6110 fingerprints. Isolated, relatively rare, random events within the M. tuberculosis genome alter molecular fingerprinting patterns with any of the methods; therefore, strains which are different by two or more typing methods are usually not considered to be closely related. In this report, we describe two strains of M. tuberculosis, obtained from the same bronchoscope 2 days apart, that demonstrated unique molecular fingerprinting patterns by two different typing methods. They were closely linked through the bronchoscope by a traditional epidemiologic investigation. Genetic analysis of the two strains revealed that a single event, the transposition of an IS6110 insertion sequence in one of the strains, accounted for both the differences in the IS6110 pattern and the apparent deletion of a spacer in the spoligotype. This finding shows that a single event can change the molecular fingerprint of a strain in two different molecular typing systems, and thus, molecular typing cannot be the only means used to track transmission of this organism through a population. Traditional epidemiologic techniques are a necessary complement to molecular fingerprinting so that radical changes within the fingerprint pattern can be identified.

Preventable childhood tuberculosis in Alabama: implications and opportunity.

UNLABELLED: Childhood tuberculosis (TB) cases indicate recent community transmission and thus reflect the effectiveness of TB control efforts, particularly the contact investigation. OBJECTIVE: To evaluate all preventable childhood TB cases and implications in the context of TB morbidity trends. DESIGN: Statewide morbidity trends are presented from 1983 to 1997. Since 1992, each child TB case is classified as either preventable or not preventable, based on a standard definition. MAIN OUTCOME MEASURES: Case characteristics (preventable and not preventable), TB disease rates over time, and reasons for preventable case classification. SETTING: Alabama TB control program, from January 1, 1983 through December 31, 1997. RESULTS: For the period 1983-1997, nonwhite children had a higher disease rate (rate ratio: 5.7; 95% confidence interval: 4.3,7.6) than white children. Since 1990, the overall child rate has increased significantly despite a decline in the adult rate. Among 120 child cases diagnosed from 1992 to 1997, 25 (21%) were classified as preventable. The causes were contact investigation interview failure (12/25 = 48%), delay to evaluation (16%), source case noncompliance with previously prescribed preventive therapy (16%), and source case diagnosed out of state (16%) with no initial investigation performed in Alabama. All preventable cases identified were black children; the proportion of preventable cases did not vary by age group or sex. During 1996, the case rate for nonwhite children exceeded that of adult whites. CONCLUSIONS: Childhood TB in Alabama for nonwhites is rising despite a national downward trend. TB is clearly a disproportionate disease burden for the state's African American population, and the median case age is falling. Additional research and improved training in contact investigation are required to assess this situation and effectively intervene.

Spot sputum screening: evaluation of an intervention in two homeless shelters.

SETTING: Two homeless shelters in Birmingham, Alabama. OBJECTIVE: To interrupt tuberculosis transmission and evaluate the utility of spot sputum screening. DESIGN: Two shelters participated in the study between May 1996 and February 1997. A spot sputum specimen was collected on a given evening from each overnight client. Information was obtained regarding symptoms and tuberculin skin test (TST) status. There were four screenings during two rounds, with TST in round one only. RESULTS: Of 127 persons involved in the study, 120 (95%) provided specimens, and four tuberculosis cases were identified (4/127, 3.1%). Symptoms were infrequently reported. RFLP analysis (IS6110) confirmed a two-band cluster in three of the four cases; another matching two-band strain was found in a drug rehabilitation client staying in one shelter. Secondary RFLP typing (pTBN12) confirmed the homeless cluster. Costs were $1311 per case identified. Among 92 clients with a prior TST, 40% reported a positive result (37/92). Of 21 PPD tests read, 11 were > or =10 mm (52%). CONCLUSION: Spot sputum screening is effective in identifying unsuspected tuberculosis cases in shelters. It has acceptable costs, is logistically simple and efficient. Symptom screening was not useful in this general homeless population. RFLP analysis showed cloning of the two-band strain. Given the evidence for ongoing transmission, sputum screening should be considered in shelter settings.

Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB.

Multidrug-resistant tuberculosis (MDR-TB) threatens the progress of global control efforts. Prisons represent a high risk setting for development and transmission of MDR-TB. In a Siberian TB referral prison (Kemerovo region), the treatment failure rate is 35% (June 1996-March 1997), despite implementation of a strict DOTS program and use of the World Health Organization Category 2 re-treatment regimen for all new cases. Among 164 patients (December 1997-March 1998), initial resistance to isoniazid and rifampin is 22.6%. Such a rate is a warning call to reconsider prison control strategies, and importantly, to address the treatment regimens necessary to combat an institutional epidemic of MDR-TB.

Restriction fragment length polymorphism screening of Mycobacterium tuberculosis isolates: population surveillance for targeting disease transmission in a community.

SETTING: Alabama State Tuberculosis Control Program, USA. OBJECTIVE: To combine molecular screening data with routine information to assess transmission of Mycobacterium tuberculosis and improve control efforts. DESIGN: Since January 1994, samples from tuberculosis cases statewide have been systematically analyzed by IS6110 restriction fragment length polymorphism (RFLP). All cases during 1994-1995 with a predominate RFLP pattern were evaluated and risk factors assessed. pTBN12 was used to evaluate a large cluster in the Birmingham-Jefferson County (BJC) area. RESULTS: Statewide, a common two-band pattern was found, named JH2 (99/566, 17.5%). The most important risk associated with this pattern was homelessness (odds ratio, 8.9; P < 0.001). In the BJC area, the homeless accounted for 29% (51/175) of new cases diagnosed during the study period. For the BJC homeless, there were 13 unique RFLP patterns, and JH2 was predominant (29/33, 88%) among three clusters. Secondary analysis of the homeless JH2 cluster revealed a large group that included 19 of 24 (79%) isolates analyzed. Compared with the BJC non homeless (n = 124), the homeless were younger (P < 0.001), of male gender (P < 0.001), black race (P = 0.002), and were heavy alcohol (P < 0.001) and non-injection drug (P = 0.001) users. CONCLUSIONS: By screening tuberculosis cases statewide, a common two-band RFLP pattern was identified. Its predominance is explained by an ongoing tuberculosis epidemic among Birmingham's homeless population, highlighting RFLP as a tool for population surveillance. The pattern differences observed by pTBN12 typing clearly demonstrate that the isolates might be related but are not clonal.

Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients.

BACKGROUND: Despite the use of directly observed therapy (DOT) by tuberculosis control programs, patient treatment failure, relapse, and acquired drug resistance remain problematic in a small number. We investigated serum drug levels in non-HIV-infected tuberculosis patients who were receiving DOT by the health department and did not respond to treatment as expected. METHODS: The indications for checking levels were as follows: (1) slow clinical response or failure to convert the sputum culture within 12 weeks; (2) treatment failure, early disease relapse < 13 months since being declared cured; (3) relapse, late disease reactivation > or = 13 months since being declared cured; and (4) acquired drug resistance while receiving DOT. Baseline characteristics of control subjects who responded to therapy as expected were compared. Venous blood for analysis was obtained at 2 h after directly observed ingestion and measured by high-performance liquid chromatography. RESULTS: Twenty-four patients receiving daily or twice-weekly standard therapy with isoniazid (INH, 300 or 900 mg) and rifampin (RMP, 600 mg) were identified; 22 had drug levels evaluated at 2 h. For INH, 15 of 22 patients (68%) had levels less than the reported target range. For RMP, 14 of 22 patients (64%) had low levels. Among the 14 patients receiving INH, 900 mg, and RMP, 600 mg, 4 (29%) had very low levels of both. Use of a combination INH/RMP tablet was associated with lower INH levels (p=0.04); however, RMP levels were higher (p<0.02). Alcohol use was associated with significantly higher RMP (p<0.01) serum concentrations. CONCLUSIONS: Important questions remain concerning the utility and timing of serum drug measurements. However, if a patient is not responding to therapy as expected and one is assured that the Mycobacterium tuberculosis organism is susceptible to the drugs given and that the patient is taking the medication as prescribed, drug level monitoring should be considered.