Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Impact of malnutrition on clinical presentation, clinical course, and mortality in MDR-TB patients.

Despite the adoption of strategies to prevent and treat multidrug-resistant tuberculosis (MDR-TB) over the past decade, Latvia continues to have one of the highest rates of MDR-TB in the world. It is important to identify modifiable factors that may impact on MDR-TB patient outcomes. A study was conducted to elucidate the association between nutritional status and clinical presentation, clinical course, and mortality in 995 adult patients treated for MDR-TB from 2000 to 2004. Twenty percent of patients were underweight, defined as a body mass index <18·5, at the time of diagnosis. These patients were significantly more likely to have clinical evidence of advanced disease, and had a greater risk of experiencing ≥3 side-effects [adjusted odds ratio 1·5, 95% confidence interval (CI) 1·1-2·1] and death (adjusted hazard ratio 1·9, 95% CI 1·1-3·5) compared to patients who were normal or overweight. Interventions aimed at these high-risk patients, including nutritional supplementation as an adjunct to anti-TB therapy, should be considered and evaluated by TB programmes.

Treatment outcome of multidrug/extensively drug-resistant tuberculosis in Latvia, 2000-2004.

In the present study, we characterised drug-resistance patterns, compared treatment outcome between extensively and nonextensively drug-resistant tuberculosis (non-XDR-TB) cases, and assessed risk factors for poor outcome in a high-prevalence country that screens all TB patients for first-line anti-TB drug resistance. We reviewed drug susceptibility test results among all pulmonary TB cases in Latvia diagnosed from 2000-2004, as well as demographic and clinical characteristics, drug-resistance patterns, and treatment outcomes. During the 5-yr period, 1,027 multidrug-resistant tuberculosis (MDR-TB) cases initiated treatment. Among all cases, the proportion that experienced an outcome of cure or completion increased from 66.2 to 70.2% (p = 0.06 for linear trend). Among the 48 (4.7%) XDR-TB cases, 18 (38%) were cured, four (8%) died, three (6%) defaulted, and treatment failed in 23 (48%). In proportional-hazards analysis, characteristics significantly associated with poor outcome included XDR-TB, being retired, presence of bilateral cavitation, and previous MDR-TB treatment history for those aged ≥55 yrs. Overall, treatment success among all MDR-TB cases increased over time. Strategies to prevent transmission of XDR-TB and to further improve treatment outcome are crucial for the future of TB control in Latvia.

Adjunctive resectional lung surgery for extensively drug-resistant tuberculosis.

Extensively drug-resistant (XDR) tuberculosis (TB) poses significant management challenges as there are limited pharmacological treatment options for cure. Adjunctive resectional lung surgery decreases case-fatality rates for some patients with multidrug-resistant tuberculosis (MDR-TB), but its use has not been well documented for patients with XDR-TB. We describe 17 XDR-TB patients treated with surgery as part of their case management in Latvia during 1999-2005. One patient had no previous TB treatment history, 10 were previously treated for drug-susceptible TB and six were previously treated for MDR-TB. Mycobacterium tuberculosis isolates from the 17 patients were resistant to a mean of 9.2 drugs. Due to failure of pharmacological therapy, one due to a large cavity and one due to pulmonary haemorrhage, 15 patients were treated with surgery. Despite failure of pharmacological treatment in 15 out of 17 patients, eight (47%) were cured with adjunctive surgical treatment. Surgery should be explored as a possible treatment option for patients with XDR-TB.

Treatment outcome cohort analysis in an integrated DOTS and DOTS-Plus TB program in Latvia.

International guidelines for treatment outcome analysis of tuberculosis cases have been published and are widely used. They do not, however, fully address the incorporation of multidrug-resistant tuberculosis (MDR-TB) cases. Here we present an approach to cohort analysis of treatment outcomes for all registered TB cases, including MDR-TB cases. We analyzed all new pulmonary smear- and/or culture-positive cases registered in Latvia during 2002. Analysis of treatment outcomes at 24 months after initial case registration showed overall treatment success at 84%. This approach to outcome analysis is possible only for settings where MDR-TB treatment is established.

Tuberculosis control in Latvia: integrated DOTS and DOTS-plus programmes.

From 1991 until the end of 1998, the number of patients with tuberculosis in Latvia increased 2.5 times with a simultaneous increase of drug resistant and multidrug resistant tuberculosis (MDR-TB). Descriptive analysis of different TB programme services, activities and strategies including Directly Observed Therapy Short-course (DOTS) for tuberculosis and treatment of MDR-TB, were performed. Data from the state tuberculosis registry, drug resistance surveillance, and the national MDR-TB database were used. The state-funded national tuberculosis control programme (NTAP, Nacionâlâ Tuberkulozes Apkarodanas Programma), based on WHO recommended DOTS strategy, was introduced in Latvia in 1996. The NTAP includes TB control in prisons. Treatment of MDR-TB using second line drugs was started in 1997. Cure rates for TB patients increased from 59.5% in 1996 to 77.5% in 2003. Between 1996 and 2003, more than 200 patients began MDR-TB treatment each year, and the cure rate was between 66% and 73%. Numbers of MDR-TB patients were reduced by more than half during this period. Treatment results including MDR-TB reached the WHO target, with cure rates 85% of newly diagnosed patients. These results demonstrate that MDR-TB treatment and management using the individualised treatment approach can be effectively provided within the overall TB programme on a national scale, to successfully treat a large number of MDR-TB patients. Rapid diagnostic methods combined with early intensified case finding, isolation and infection control measures could decrease transmission of TB and MDR-TB in hospitals and in the community. Highly important that MDR-TB management follows WHO recommendations in order to stop creating drug resistance to first and to second line drugs.

Tuberculosis control in Latvia: integrated DOTS and DOTS-plus programmes.

From 1991 until the end of 1998, the number of patients with tuberculosis in Latvia increased 2.5 times with a simultaneous increase of drug resistant and multidrug resistant tuberculosis (MDR-TB). Descriptive analysis of different TB programme services, activities and strategies including Directly Observed Therapy Short-course (DOTS) for tuberculosis and treatment of MDR-TB, were performed. Data from the state tuberculosis registry, drug resistance surveillance, and the national MDR-TB database were used. The state-funded national tuberculosis control programme (NTAP, Nacionala Tuberkulozes Apkarodanas Programma), based on WHO recommended DOTS strategy, was introduced in Latvia in 1996. The NTAP includes TB control in prisons. Treatment of MDR-TB using second line drugs was started in 1997. Cure rates for TB patients increased from 59.5% in 1996 to 77.5% in 2003. Between 1996 and 2003, more than 200 patients began MDR-TB treatment each year, and the cure rate was between 66% and 73%. Numbers of MDR-TB patients were reduced by more than half during this period. Treatment results including MDR-TB reached the WHO target, with cure rates 85% of newly diagnosed patients. These results demonstrate that MDR-TB treatment and management using the individualised treatment approach can be effectively provided within the overall TB programme on a national scale, to successfully treat a large number of MDR-TB patients. Rapid diagnostic methods combined with early intensified case finding, isolation and infection control measures could decrease transmission of TB and MDR-TB in hospitals and in the community. Highly important that MDR-TB management follows WHO recommendations in order to stop creating drug resistance to first and to second line drugs.

Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis.

SETTING: Globally it is estimated that 273000 new cases of multidrug-resistant tuberculosis (MDR-TB, resistance to isoniazid and rifampicin) occurred in 2000. To address MDR-TB management in the context of the DOTS strategy, the World Health Organization and partners have been promoting an expanded treatment strategy called DOTS-Plus. However, standard definitions for MDR-TB patient registration and treatment outcomes do not exist. OBJECTIVE: To propose a standardized set of case registration groups and treatment outcome definitions for MDR-TB and procedures for conducting cohort analyses under the DOTS-Plus strategy. DESIGN: Using published definitions for drug-susceptible TB as a guide, a 2-year-long series of meetings, conferences, and correspondence was undertaken to review published literature and country-specific program experience, and to develop international agreement. RESULTS: Definitions were designed for MDR-TB patient categorization, smear and culture conversion, and treatment outcomes (cure, treatment completion, death, default, failure, transfer out). Standards for conducting outcome analyses were developed to ensure comparability between programs. CONCLUSION: Optimal management strategies for MDR-TB have not been evaluated in controlled clinical trials. Standardized definitions and cohort analyses will facilitate assessment and comparison of program performance. These data will contribute to the evidence base to inform decision makers on approaches to MDR-TB control.

[Risk factors for early relapse of tuberculosis in Latvia].

OBJECTIVE: To evaluate risk factors for tuberculosis relapse within a short time after successful tuberculosis treatment among Latvian patients treated in 1996. DESIGN: Retrospective case-control study of tuberculosis patients diagnosed and treated successfully in 1996. RESULTS: 48 cases and 96 matched controls were included in the study. 18 cases and 22 controls had documentation of at least one interruption (OR 2.96; 95% CI 1.09-7.99). Early relapse was not associated with type of treatment facility, age or unemployment, but was positively associated with alcohol use (OR 17.70; 95% CI 4.14-75.77). In a multivariate analysis, only alcohol use was significantly associated with early relapse (OR 16.63; 95% CI 3.63-76.10). CONCLUSION: Alcohol use was the main risk factor for early tuberculosis relapse.

Impact of the growing HIV-1 epidemic on multidrug-resistant tuberculosis control in Latvia.

Latvia, a country with levels of multidrug-resistant (MDR) TB among the highest in the world, experienced a 58-fold increase in HIV seroprevalence among all persons tested in the country from 1996 through 2001. In addition, HIV seroprevalence among TB cases increased from 0.4% to 1.4%, and among MDR-TB cases from 0% to 5.6% from 1998 through 2001, potentially compromising gains made to date in controlling the country's MDR-TB epidemic. The following will be critical to the future of MDR-TB control in Latvia: containing HIV transmission in the country, particularly among injection drug users who comprised 72% of all HIV cases reported in the country by the end of 2001, as well as 81% of all MDR-TB cases co-infected with HIV; expanding capabilities to more rapidly detect and successfully treat patients with MDR-TB; developing mutual TB control strategies between the National TB and AIDS programs; and continuing to improve institutional infection control measures, particularly in hospitals and prisons where an increasing number of persons infected with HIV come into contact with persons with active MDR-TB.

Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-Plus initiative.

Adverse events associated with second-line drugs have been mentioned as obstacles in the management of multidrug-resistant tuberculosis (MDR-TB). Data on adverse events were collected from five DOTS-Plus sites in Estonia, Latvia, Peru (Lima), the Philippines (Manila) and the Russian Federation (Tomsk Oblast). The results show that among 818 patients enrolled on MDR-TB treatment only 2% of patients stopped treatment, but 30% required removal of the suspected drug(s) from the regimen due to adverse events. The study shows that adverse events are manageable in the treatment of MDR-TB in resource-limited settings provided that standard management strategies are applied.

Multi- and extensively drug-resistant tuberculosis in Latvia: trends, characteristics and treatment outcomes.

SETTING: Drug-resistant tuberculosis (TB) is an important public health problem in Latvia. OBJECTIVE: To document trends, characteristics and treatment outcomes of registered patients with multi-drug-resistant (MDR-) and extensively drug-resistant (XDR-) TB in Latvia from 2000 to 2010. DESIGN: A retrospective national cohort study. RESULTS: Of 1779 patients, 1646 (92%) had MDR- and 133 (8%) XDR-TB. Over 11 years, the proportion of XDR-TB among MDR-TB patients increased from 2% to 18%. Compared to MDR-TB patients, those with XDR-TB were significantly more likely to have failed MDR-TB treatment (OR 8.4, 95%CI 4.3-16.2), have human immunodeficiency virus infection (OR 3.2, 95%CI 1.8-5.7), be illegal drug users (OR 5.7, 95%CI 2.6-11.6) or have had contact with MDR-TB patients (OR 1.9, 95%CI 1.3-2.8). Cure rates for XDR-TB were 50%. Compared with MDR-TB patients, those with XDR-TB had a higher risk of treatment failure (29% vs. 8%, respectively, P < 0.001). Unfavourable treatment outcomes were significantly associated with being male; having smear-positive disease; pulmonary cavities; failure, default or relapse after previous MDR-TB treatment; and a history of incarceration. CONCLUSION: More MDR-TB in Latvia is now also XDR-TB. This study identified several risk factors for XDR-TB and, for unfavourable treatment outcomes, highlighting the importance of early diagnosis and appropriate management of MDR-/XDR-TB.

Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis.

OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment.

Implementation of the INNO-LiPA Rif. TB® line-probe assay in rapid detection of multidrug-resistant tuberculosis in Latvia.

SETTING: In Latvia, 11% of tuberculosis (TB) patients have multidrug-resistant TB (MDR-TB). The INNO-LiPA Rif.TB ® line-probe assay (LPA) detects rifampin (RMP) resistance and may accelerate the time to effective MDRTB treatment. OBJECTIVE: To determine the impact of LPA on time to diagnosis, initiation of treatment, sputum culture conversion and treatment outcome. DESIGN: From October 2004 to September 2006, we performed LPA and drug susceptibility testing (DST) using BACTEC and Löwenstein-Jensen (LJ) media among all individuals at risk for MDR-TB compared to a 2003 cohort of 48 MDR-TB patients detected by BACTEC. RESULTS: In a total of 107 sputum smear-positive individuals at risk for MDR-TB, Mycobacterium tuberculosis was isolated from 85; 23 were RMP-resistant on LJ compared to 22 on LPA (96% sensitivity). There was a significant difference in the mean time between specimen collection and LPA result (10.0 days) and BACTEC DST result (17.0 days, P = 0.0005) in the LPA cohort. The LPA cohort achieved culture conversion a median of 105 days after treatment initiation vs. a median of 88.5 days (P = 0.54) in the BACTEC cohort. There was no difference in the proportion achieving culture conversion (P = 0.54) or in treatment outcome ( P = 0.65). CONCLUSION: LPA accelerated empiric treatment, but did not reduce the time to culture conversion or improve the rate of culture conversion or treatment outcome.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment.

Monthly culture is usually recommended to monitor treatment of multidrug-resistant tuberculosis (MDR-TB). As mycobacterial laboratory capacity is limited in many settings, TB programs need evidence to decide whether monthly cultures are necessary compared to other approaches. We simulated three alternative monitoring strategies (culture every 2 or 3 months, and monthly smears alone) in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru from 2000 to 2004. This retrospective analysis illustrated that less frequent testing delays confirmation of bacteriological conversion. This would prolong intensive treatment, hospitalization and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects.

BACKGROUND: Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. OBJECTIVES: To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. DESIGN: Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. RESULTS: Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustained culture conversion. Median time to culture conversion was 3 months. Among 206 patients whose nal conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. CONCLUSIONS: Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with de ned end points for treatment failure. The interval between rst and nal conversion among patients whose initial con- version is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure.

Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000-2004.

SETTING: Latvia has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) globally. Clinical management of MDR-TB requires lengthy multidrug regimens that often cause adverse events. DESIGN: We retrospectively reviewed records of patients who began MDR-TB treatment between 2000 and 2004. Treatment-related adverse events and factors associated with experiencing adverse events were evaluated. We also examined the frequency of and reasons for changing drug regimens. RESULTS: Among 1027 cases, 807 (79%) experienced at least one adverse event, with a median of three events per case. The most commonly reported events were nausea (58%), vomiting (39%) and abdominal pain (24%). More serious events, such as psychiatric episodes (13%), hepatitis (9%) and renal failure (4%), were relatively frequent. A change in drug dose due to an adverse event occurred in 201 (20%) cases, while 661 (64%) had at least one drug discontinued temporarily or permanently. Being older, female, having bilateral lung cavities and a greater number of TB symptoms at baseline were associated with an increased number of events. CONCLUSION: Adverse events were prevalent among MDR-TB cases treated in Latvia, with over two thirds requiring discontinuation of at least one drug. MDR-TB patients who are female, older or have severe TB disease should be closely monitored for treatment-related adverse events.