An algorithm for tuberculosis screening and diagnosis in people with HIV.

BACKGROUND: Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS: We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS: Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS: In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Nontuberculous mycobacterial disease in patients with HIV in Southeast Asia.

RATIONALE: Although nontuberculous mycobacteria (NTM) are widely documented as a cause of illness among HIV-infected people in the developed world, studies describing the prevalence of NTM disease among HIV-infected people in most resource-limited settings are rare. OBJECTIVES: To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia. METHODS: We enrolled people with HIV from three countries in Southeast Asia and collected pulmonary and extrapulmonary specimens to evaluate the prevalence of mycobacterial disease. We adapted American Thoracic Society/Infectious Disease Society of America guidelines to classify patients into NTM pulmonary disease, NTM pulmonary disease suspects, NTM disseminated disease, and no NTM categories. MEASUREMENTS AND MAIN RESULTS: In Cambodia, where solid media alone was used, NTM was rare. Of 1,060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had tuberculosis and 218 (21%) had NTM. Of 218 patients with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM disease was 2% (19 of 1,060). Of 51 patients receiving antiretroviral therapy (ART), none had NTM disease compared with 19 (2%) of 1,009 not receiving ART. CONCLUSIONS: Although people with HIV frequently have sputum cultures positive for NTM, few meet a strict case definition for NTM disease. Consistent with previous studies, ART was associated with lower odds of having NTM disease. Further studies of NTM in HIV-infected individuals in tuberculosis-endemic countries are needed to develop and validate case definitions.

Which new diagnostics for tuberculosis, and when?

Recently, new diagnostic tools for tuberculosis detection and resistance testing have become available. The World Health Organization endorses new tuberculosis diagnostics by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. This endorsement process takes place when limited evidence beyond test accuracy is available. There is a need to provide guidance to tuberculosis programs about which new diagnostics to scale up and how best to position them in diagnostic algorithms. To speed adoption of new diagnostics for tuberculosis, the policy recommendation process should be revised to consist of 2 steps: technical recommendation and programmatic recommendation. Technical recommendation would follow the GRADE process and be based on accuracy with limited cost and feasibility data, while programmatic recommendation would include patient-important outcomes, cost-effectiveness when implemented under routine conditions, and factors critical to successful scale-up. The evidence for both steps should be systematically collected, but each requires different study designs.

Clinical research and development of tuberculosis diagnostics: moving from silos to synergy.

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations.

Extensive drug resistance in malaria and tuberculosis.

Drug resistance in malaria and in tuberculosis (TB) are major global health problems. Although the terms multidrug-resistant TB and extensively drug-resistant TB are precisely defined, the term multidrug resistance is often loosely used when discussing malaria. Recent declines in the clinical effectiveness of antimalarial drugs, including artemisinin-based combination therapy, have prompted the need to revise the definitions of and/or to recategorize antimalarial drug resistance to include extensively drug-resistant malaria. Applying precise case definitions to different levels of drug resistance in malaria and TB is useful for individual patient care and for public health.

Bloodstream infections among HIV-infected outpatients, Southeast Asia.

Bloodstream infections (BSIs) are a major cause of illness in HIV-infected persons. To evaluate prevalence of and risk factors for BSIs in 2,009 HIV-infected outpatients in Cambodia, Thailand, and Vietnam, we performed a single Myco/F Lytic blood culture. Fifty-eight (2.9%) had a clinically significant BSI (i.e., a blood culture positive for an organism known to be a pathogen). Mycobacterium tuberculosis accounted for 31 (54%) of all BSIs, followed by fungi (13 [22%]) and bacteria (9 [16%]). Of patients for whom data were recorded about antiretroviral therapy, 0 of 119 who had received antiretroviral therapy for ≥14 days had a BSI, compared with 3% of 1,801 patients who had not. In multivariate analysis, factors consistently associated with BSI were fever, low CD4+ T-lymphocyte count, abnormalities on chest radiograph, and signs or symptoms of abdominal illness. For HIV-infected outpatients with these risk factors, clinicians should place their highest priority on diagnosing tuberculosis.

Tuberculosis co-morbidity and perceptions about health care among HIV-infected plasma donors in rural China.

Limited community-based data exist about pulmonary tuberculosis (TB) comorbidity among HIV-infected individuals in China and no data exists about the TB burden in key high risk groups. We recruited 195 known HIV-infected plasma donors in one central China county and identified 9 (4.6%) active TB cases based on clinical assessment, including chest radiography. The low percentage of TB may be explained by improved immunity due to antiretroviral therapy.

Clinical evaluation of the microscopic-observation drug-susceptibility assay for detection of tuberculosis.

BACKGROUND: There is an urgent need for low-cost methods for rapid, accurate detection of Mycobacterium tuberculosis in clinical specimens. The microscopic-observation drug-susceptibility (MODS) assay is a relatively low-cost and simple liquid culture method that has been proposed for use in resource-limited environments. METHODS: This prospective study evaluated the performance of the MODS assay for detection of M. tuberculosis in persons undergoing evaluation for pulmonary tuberculosis in Brazil and Honduras. Respiratory specimens were evaluated using smear microscopy, culture on Lowenstein-Jensen medium, and culture using the MODS assay. A subset of specimens was also cultured using the Mycobacterial Growth Indicator Tube (MGIT) 960 automated system (Becton Dickinson). A study subject was considered to have tuberculosis if at least 1 culture on Lowenstein-Jensen medium was positive for M. tuberculosis. FINDINGS: A total of 1639 respiratory specimens obtained from 854 study subjects were analyzed. On a per-subject basis, MODS sensitivity was 97.5% (95% confidence interval [CI], 95.7-98.6), and specificity was 94.4% (95% CI, 93.1-95.2). Median times to detection were 21 days (interquartile range [IQR], 17-25 days) and 7 days (IQR, 5-10) for culture on Lowenstein-Jensen medium and for the MODS assay, respectively (P<.01). For 64 specimens cultured using the MGIT 960 automated system, median time to growth was similar for the MODS assay (7 days; IQR, 7-10 days) and the MGIT 960 automated system (8 days; IQR, 6-11.5 days; P=.16). The percentage of contaminated cultures was lower for the MODS assay than for culture on Lowenstein-Jensen medium (3.8% vs. 5.8%; P<.01). CONCLUSIONS: The MODS assay is a relatively simple test whose good performance characteristics for detection of pulmonary tuberculosis may make it suitable for resource-limited environments.

Feasibility of achieving the 2025 WHO global tuberculosis targets in South Africa, China, and India: a combined analysis of 11 mathematical models.

BACKGROUND: The post-2015 End TB Strategy proposes targets of 50% reduction in tuberculosis incidence and 75% reduction in mortality from tuberculosis by 2025. We aimed to assess whether these targets are feasible in three high-burden countries with contrasting epidemiology and previous programmatic achievements. METHODS: 11 independently developed mathematical models of tuberculosis transmission projected the epidemiological impact of currently available tuberculosis interventions for prevention, diagnosis, and treatment in China, India, and South Africa. Models were calibrated with data on tuberculosis incidence and mortality in 2012. Representatives from national tuberculosis programmes and the advocacy community provided distinct country-specific intervention scenarios, which included screening for symptoms, active case finding, and preventive therapy. FINDINGS: Aggressive scale-up of any single intervention scenario could not achieve the post-2015 End TB Strategy targets in any country. However, the models projected that, in the South Africa national tuberculosis programme scenario, a combination of continuous isoniazid preventive therapy for individuals on antiretroviral therapy, expanded facility-based screening for symptoms of tuberculosis at health centres, and improved tuberculosis care could achieve a 55% reduction in incidence (range 31-62%) and a 72% reduction in mortality (range 64-82%) compared with 2015 levels. For India, and particularly for China, full scale-up of all interventions in tuberculosis-programme performance fell short of the 2025 targets, despite preventing a cumulative 3·4 million cases. The advocacy scenarios illustrated the high impact of detecting and treating latent tuberculosis. INTERPRETATION: Major reductions in tuberculosis burden seem possible with current interventions. However, additional interventions, adapted to country-specific tuberculosis epidemiology and health systems, are needed to reach the post-2015 End TB Strategy targets at country level. FUNDING: Bill and Melinda Gates Foundation.

Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action.

New tuberculosis drug regimens are creating new priorities for drug susceptibility testing (DST) and surveillance. To minimise turnaround time, rapid DST will need to be prioritised, but developers of these assays will need better data about the molecular mechanisms of resistance. Efforts are underway to link mutations with drug resistance and to develop strain collections to enable assessment of new diagnostic assays. In resource-limited settings, DST might not be appropriate for all patients with tuberculosis. Surveillance data and modelling will help country stakeholders to design appropriate DST algorithms and to decide whether to change drug regimens. Finally, development of practical DST assays is needed so that, in countries where surveillance and modelling show that DST is advisable, these assays can be used to guide clinical decisions for individual patients. If combined judiciously during both development and implementation, new tuberculosis regimens and new DST assays have enormous potential to improve patient outcomes and reduce the burden of disease.

Use of anti-retroviral therapy in tuberculosis patients on second-line anti-TB regimens: a systematic review.

INTRODUCTION: Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB. METHODS: We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events. RESULTS: Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6-7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3-0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm(3) and less than 50 cells/mm(3), and when correcting for drug resistance pattern. LIMITATIONS: We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias. DISCUSSION: While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.

Size and usage patterns of private TB drug markets in the high burden countries.

BACKGROUND: Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries--Pakistan, the Philippines, Indonesia and India--had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65-117% of the respective countries' estimated annual incident cases with a standard 6-8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2-11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB). CONCLUSIONS/SIGNIFICANCE: Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs.

Voluntary counselling and testing uptake and HIV prevalence among tuberculosis patients in Jogjakarta, Indonesia.

We aimed to establish HIV prevalence and uptake of unlinked anonymous testing and voluntary counselling and testing (VCT) among tuberculosis (TB) patients in Jogjakarta, Indonesia. We introduced unlinked anonymous HIV testing for TB patients attending directly observed treatment, short-course services between April and December 2006. Patients were additionally offered VCT services. Of 1269 TB patients who were offered unlinked anonymous testing, 989 (77.9%; 95% CI 75.6-80.1%) accepted. HIV prevalence was 1.9% (95% CI 1.6-2.2%). HIV infections were less frequently diagnosed among TB patients who attended a public health centre [odds ratio (OR) 0.15; 95% CI 0.03-0.70] rather than public hospital. They were more frequent in TB patients with a university education background (OR 5.16; 95% CI 1.01-26.63) or a history of HIV testing (OR 57.87; 95% CI 9.42-355.62). Of the 989 patients who accepted unlinked anonymous testing, only 133 (13.4%; 95% CI 11.5-15.7%) expressed interest in VCT. Of these, 52 (39.1%; 95% CI 31.2-47.6%) attended VCT, but interest was higher among students and those offered VCT by public health centres. The HIV prevalence in Jogjakarta is higher than expected and needs to be monitored cautiously. Unlinked anonymous HIV testing is well accepted and can be implemented with modest additional efforts.

Clinical evaluation of the microscopic observation drug susceptibility assay for detection of Mycobacterium tuberculosis resistance to isoniazid or rifampin.

This prospective study evaluated the performance of the microscopic observation drug susceptibility (MODS) assay for the direct detection of Mycobacterium tuberculosis drug resistance. MODS assay sensitivity, specificity, and positive and negative predictive values were 96.7% (95% confidence interval [95% CI], 92.1 to 98.8%), 78.4% (95% CI, 73.5 to 80.6%), 82.4% (95% CI, 78.4 to 84.2%), and 95.8% (95% CI, 89.9 to 98.5%), respectively, for isoniazid resistance and 96.0% (95% CI, 90.3 to 98.6%), 82.9% (95% CI, 78.8 to 84.7%), 80.0% (95% CI, 75.2 to 82.1%), and 96.7% (95% CI, 91.9 to 98.8%), respectively, for rifampin resistance. For both rifampin and isoniazid testing, the likelihood ratio for a negative test was < or =0.05, indicating that the MODS assay may be useful for ruling out drug resistance.

Long-term molecular analysis of tuberculosis strains in alabama, a state characterized by a largely indigenous, low-risk population.

With a tuberculosis case detection rate of 5.9 per 100,000 population in 2001, Alabama ranked twelfth highest in the United States. However, cases among foreign-born and human immunodeficiency virus-infected individuals remain low in Alabama. To understand the endemic statewide disease pattern, tuberculosis strains were studied for clustering in a long-term population-based study from January 1994 to May 2000. IS6110 restriction fragment length polymorphism analysis was performed for 1,834 strains. Spoligotyping was used as a secondary typing method for the 37% of isolates displaying a restriction fragment length polymorphism pattern with <6 IS6110 copies. A total of 721 (41%) patients provided isolates that composed 114 clusters, each containing isolates from 2 to 136 patients, suggesting that recent transmission accounted for 35% of tuberculosis cases. Demographic, behavioral, and clinical characteristics of patients with clustered versus nonclustered isolates stratified by low-copy-number strains (<6 IS6110 copies) versus high-copy-number strains (> or =6 IS6110 copies) were evaluated. Younger age, black race, a history of alcohol abuse, and homelessness were predictors of clustering of low-copy-number, strains and younger age, urban residency, alcohol abuse, homelessness, noninjection drug use, and a history of incarceration and/or cavitary disease were predictors of clustering of high-copy-number strains. By identifying local characteristics of tuberculosis clustering through molecular fingerprinting, control programs can distribute their limited resources to impact the transmission of tuberculosis in high-risk populations and evaluate strain distribution across geographical areas.

Decentralization of the DOTS programme within a Russian penitentiary system. How to ensure the continuity of tuberculosis treatment in pre-trial detention centres.

BACKGROUND: In Kemerovo region (Siberia), three pre-trial detention centres (SIZO; Ministry of Justice) serve as the gateway to the penitentiary system, comprised of 23 prisons and 30,000 detainees. The follow-up for tuberculosis (TB) patients released into civil society is unreliable. Due to varying detention times and frequent transfers to temporary detention centres (IVS; Ministry of Internal Affairs) for investigation and trial, and concerns about continuity of treatment, SIZOs were not included in the revised TB control programme initiated during 1996. METHODS: To investigate the feasibility of DOTS (Directly Observed Therapy, Short-Course) expansion into SIZOs, general detainee release was studied by examining 10% of files from detainees admitted during 1998 (SIZOs 1,2,3). Then, 5% of general files from SIZO 1 were examined to determine SIZO-IVS flow; 224 TB patient files from SIZO 3 were evaluated to determine the pattern of release/transfer. RESULTS: TB patients in SIZO 3 have less chance of release before six months of detention than non-TB detainees (14/224, 6.3% versus 774/2276, 34%; p < 0.001). Among detainees not released, 60% are not moved during the first six months of detention. For those who move, the mean stay in IVS was 9.5 (+/- 6) days. The incidence of active disease detected upon entry to SIZO 3 was 4,560/100,000, the subsequent rate during the same year of detention 880/100,000. CONCLUSION: Despite frequent detainee movements between institutions, DOTS should be introduced into the earliest stages of detention to prevent case mismanagement, and links to the civilian programme should be developed.

A decision tree for tuberculosis contact investigation.

The University of Alabama at Birmingham and the Alabama Department of Public Health recently developed a logistic regression model showing those variables that are most likely to predict a positive tuberculin skin test in contacts of tuberculosis cases. However, translating such a model into field application requires a stepwise approach. This article describes a decision tree developed to assist public health workers in determining which contacts are most likely to have a positive tuberculin skin test. The Classification and Regression Tree analysis was performed on 292 consecutive cases and their 2,941 contacts seen by the Alabama Department of Public Health from January 1, 1998, to October 15, 1998. Several decision trees were developed and were then tested using prospectively collected data from 366 new tuberculosis cases and their 3,162 contacts from October 15, 1998, to April 30, 2000. Testing showed the trees to have sensitivities of 87-94%, specificities of 22-28%, and false-negative rates between 7 and 10%. The use of the decision trees would decrease the number of contacts investigated by 17-25% while maintaining a false-negative rate that was close to that of the presumed background rate of latent tuberculosis infection in the state of Alabama.