Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

BACKGROUND: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. METHODS AND FINDINGS: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). CONCLUSIONS: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.

Development of extensively drug-resistant tuberculosis during multidrug-resistant tuberculosis treatment.

RATIONALE: Extensively drug-resistant (XDR) tuberculosis (TB) may arise in individuals on treatment for multidrug-resistant (MDR) TB. Preventing this amplification of resistance will likely improve clinical outcomes and delay the secondary spread of XDR-TB. OBJECTIVES: To measure the proportion of individuals that develops XDR-TB during the course of MDR-TB treatment, and to identify those factors associated with the development of XDR. METHODS: We performed a retrospective analysis of 608 consecutive patients with documented MDR-TB who were started on MDR-TB treatment between September 10, 2000 and November 1, 2004 in the Tomsk Oblast TB Treatment Services in Western Siberia, Russian Federation. MEASUREMENTS AND MAIN RESULTS: A total of 6% of patients were observed to develop XDR-TB while on MDR-TB treatment. These patients were significantly less likely to be cured or to complete treatment. Using Cox proportional hazard models, we found that the presence of bilateral and cavitary lesions was associated with a greater than threefold increase in hazard (adjusted hazard ratio [HR], 3.47; 95% confidence interval [CI], 1.32-9.14). Prior exposure to a second-line injectable antibiotic was associated with a greater than threefold increase in hazard (adjusted HR, 3.65; 95% CI, 1.81-7.37), and each additional month in which a patient failed to take at least 80% of their prescribed drugs was associated with nearly an additional 20% hazard of developing XDR-TB (adjusted HR, 1.17; 95% CI, 1.01-1.35). CONCLUSIONS: Early and rapid diagnosis, timely initiation of appropriate therapy, and programmatic efforts to optimize treatment adherence during MDR-TB therapy are crucial to avoiding the generation of excess XDR-TB in MDR-TB treatment programs.

Integrated Management of Physician-delivered Alcohol Care for Tuberculosis Patients: Design and Implementation.

BACKGROUND: While the integration of alcohol screening, treatment, and referral in primary care and other medical settings in the U.S. and worldwide has been recognized as a key health care priority, it is not routinely done. In spite of the high co-occurrence and excess mortality associated with alcohol use disorders (AUDs) among individuals with tuberculosis (TB), there are no studies evaluating effectiveness of integrating alcohol care into routine treatment for this disorder. METHODS: We designed and implemented a randomized controlled trial (RCT) to determine the effectiveness of integrating pharmacotherapy and behavioral treatments for AUDs into routine medical care for TB in the Tomsk Oblast Tuberculosis Service (TOTBS) in Tomsk, Russia. Eligible patients are diagnosed with alcohol abuse or dependence, are newly diagnosed with TB, and initiating treatment in the TOTBS with Directly Observed Therapy-Short Course (DOTS) for TB. Utilizing a factorial design, the Integrated Management of Physician-delivered Alcohol Care for Tuberculosis Patients (IMPACT) study randomizes eligible patients who sign informed consent into 1 of 4 study arms: (1) Oral Naltrexone + Brief Behavioral Compliance Enhancement Therapy (BBCET) + treatment as usual (TAU), (2) Brief Counseling Intervention (BCI) + TAU, (3) Naltrexone + BBCET + BCI + TAU, or (4) TAU alone. RESULTS: Utilizing an iterative, collaborative approach, a multi-disciplinary U.S. and Russian team has implemented a model of alcohol management that is culturally appropriate to the patient and TB physician community in Russia. Implementation to date has achieved the integration of routine alcohol screening into TB care in Tomsk; an ethnographic assessment of knowledge, attitudes, and practices of AUD management among TB physicians in Tomsk; translation and cultural adaptation of the BCI to Russia and the TB setting; and training and certification of TB physicians to deliver oral naltrexone and brief counseling interventions for alcohol abuse and dependence as part of routine TB care. The study is successfully enrolling eligible subjects in the RCT to evaluate the relationship of integrating effective pharmacotherapy and brief behavioral intervention on TB and alcohol outcomes, as well as reduction in HIV risk behaviors. CONCLUSIONS: The IMPACT study utilizes an innovative approach to adapt 2 effective therapies for treatment of alcohol use disorders to the TB clinical services setting in the Tomsk Oblast, Siberia, Russia, and to train TB physicians to deliver state of the art alcohol pharmacotherapy and behavioral treatments as an integrated part of routine TB care. The proposed treatment strategy could be applied elsewhere in Russia and in other settings where TB control is jeopardized by AUDs. If demonstrated to be effective, this model of integrating alcohol interventions into routine TB care has the potential for expanded applicability to other chronic co-occurring infectious and other medical conditions seen in medical care settings.

Alcohol consumption among men and women with tuberculosis in Tomsk, Russia.

Drinking behavior among Russian women remains poorly described. We analyzed gender differences in alcohol use among 374 tuberculosis patients in Tomsk, Siberia. Twenty-six (28.3%) women had lifetime alcohol abuse or dependence, compared with 70.6% of men. Women with alcohol use disorders drank 12.7 +/- 14.0 standard drinks per day and > or = 34.6% drank 2 three days per week. Among individuals with a lifetime alcohol use disorder, age of onset and typical consumption did not differ significantly by gender. We conclude that Russian women with alcohol use disorders consume almost as much alcohol as men and may be at greater risk for negative social and medical consequences.

Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study.

BACKGROUND: Mycobacterium tuberculosis strains that cause untreatable drug-resistant disease are a threat worldwide. We describe the treatment, management, and outcomes of patients with extensively drug-resistant tuberculosis in Tomsk, Russia. METHODS: We undertook a retrospective cohort study of 608 patients with multidrug resistant tuberculosis who had treatment in civilian or prison services, between Sept 10, 2000, and Nov 1, 2004, according to the treatment strategy recommended by WHO. Clinical characteristics, management practices, and treatment outcomes of patients with extensively drug-resistant (XDR) tuberculosis and non-extensively drug-resistant (non-XDR) tuberculosis are described. The main outcome was the frequency of poor and favourable outcomes at the end of treatment. FINDINGS: Of 608 patients with multidrug resistant tuberculosis, 29 (4.8%) patients had baseline XDR tuberculosis. Treatment failure was more common in patients with XDR tuberculosis than in those with non-XDR tuberculosis (31%vs 8.5%, p=0.0008). 48.3% of patients with XDR tuberculosis and 66.7% of patients with non-XDR tuberculosis had treatment cure or completion (p=0.04). The frequency and management of adverse events did not differ between patients with XDR and non-XDR tuberculosis. INTERPRETATION: The chronic features of tuberculosis in these patients suggest that extensively drug-resistant tuberculosis may be acquired through previous treatments that include second-line drugs. Aggressive management of this infectious disease is feasible and can prevent high mortality rates and further transmission of drug-resistant strains of Mycobacterium tuberculosis.

Integration of alcohol use disorders identification and management in the tuberculosis programme in Tomsk Oblast, Russia.

Alcohol use disorders (AUDs) among tuberculosis (TB) patients are associated with nonadherence and poor treatment outcomes. We developed a multidisciplinary model to manage AUDs among TB patients in Tomsk, Russia. First, we assessed current standards of care through stakeholder meetings and ethnographic work. The Alcohol Use Disorders Identification Test (AUDIT) was incorporated into routine assessment of all patients starting TB treatment. We established treatment algorithms based on AUDIT scores. We then hired specialists and addressed licensing requirements to provide on-site addictions care. Our experience offers a successful model in the management of co-occurring AUDs among patients with chronic medical problems.

Knowledge, attitudes, and practices of physicians in Tomsk Oblast tuberculosis services regarding alcohol use among tuberculosis patients in Tomsk, Russia.

In recent years, the Russian Federation has seen a dramatic rise in morbidity and mortality from tuberculosis (TB), attributed in part to an increase in alcohol use disorders (AUDs), which are associated with worse TB treatment outcomes. This study describes the knowledge, attitudes and practices of physicians who treat TB patients in Tomsk, Russia. We conducted semistructured interviews with 16 TB physicians and 1 addiction specialist. Interviews were audiorecorded, transcribed, translated and systematically analyzed. We identified four key domains: definitions of alcohol use and abuse and physicians' knowledge, attitudes and practices regarding these problems. Physicians described patients as largely precontemplative and reluctant to seek treatment. Physicians recognized their limited knowledge in diagnosing and treating AUDs but expressed interest in acquiring these skills. Few options are currently available for treatment of AUDs in TB patients in Tomsk. These findings suggest that Tomsk physicians are aware of the need to engage AUDs in TB patients but identify a knowledge gap that restricts their ability to do so. Training TB physicians to use simple screening instruments and deliver evidence-based alcohol interventions improves TB outcomes among patients with co-occurring AUDs.

Implementing evidence-based alcohol interventions in a resource-limited setting: novel delivery strategies in Tomsk, Russia.

Effective implementation of evidence-based interventions in "real-world" settings can be challenging. Interventions based on externally valid trial findings can be even more difficult to apply in resource-limited settings, given marked differences-in provider experience, patient population, and health systems-between those settings and the typical clinical trial environment. Under the auspices of the Integrated Management of Physician-Delivered Alcohol Care for Tuberculosis Patients (IMPACT) study, a randomized, controlled effectiveness trial, and as an integrated component of tuberculosis treatment in Tomsk, Russia, we adapted two proven alcohol interventions to the delivery of care to 200 patients with alcohol use disorders. Tuberculosis providers performed screening for alcohol use disorders and also delivered naltrexone (with medical management) or a brief counseling intervention either independently or in combination as a seamless part of routine care. We report the innovations and challenges to intervention design, training, and delivery of both pharmacologic and behavioral alcohol interventions within programmatic tuberculosis treatment services. We also discuss the implications of these lessons learned within the context of meeting the challenge of providing evidence-based care in resource-limited settings.