[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · May 2014 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: Delayed diagnosis of tuberculosis (TB) increases mortality.
To evaluate whether stool culture improves the diagnosis of TB in people living with the human immunodeficiency virus (PLHIV).
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.
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).
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.
No preview · Article · Aug 2013 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Mar 2013 · The Lancet Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Apr 2012 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Apr 2012 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: 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.
To evaluate the prevalence of mycobacterial disease in HIV-infected patients in Southeast Asia.
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.
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.
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.
Full-text · Article · Feb 2012 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
[Show abstract][Hide abstract] ABSTRACT: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule.
We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%).
Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Oct 2010 · Emerging Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: We aimed to evaluate the incremental cost-effectiveness of engaging private practitioners (PPs) to refer tuberculosis (TB) suspects to public health centers in Jogjakarta, Indonesia. Effectiveness was assessed for TB suspects notified between May 2004 and April 2005. Private practitioners referred 1,064 TB suspects, of which 57.5% failed to reach a health center. The smear-positive rate among patients reaching a health center was 61.8%. Two hundred eighty (280) out of a total of 1,306 (21.4%) new smear-positive cases were enrolled through the PPs strategy. The incremental cost-effectiveness ratio per smear-positive case successfully treated for the PPs strategy was US$351.66 (95% CI 322.84-601.33). On the basis of an acceptability curve using the National TB control program's willingness-to-pay threshold (US$448.61), we estimate the probability that the PPs strategy is cost-effective at 66.8%. The strategy of engaging PPs was incrementally cost-effective, although under specific conditions, most importantly a well-functioning public directly observed treatment, short-course (DOTS) program.
Full-text · Article · Jun 2010 · The American journal of tropical medicine and hygiene
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Full-text · Article · Feb 2010 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Standard short course chemotherapy is recommended by the World Health Organization to control tuberculosis worldwide. However, in settings with high drug resistance, first line standard regimens are linked with high treatment failure. We evaluated treatment outcomes after standardized chemotherapy with the WHO recommended category II retreatment regimen in a prison with a high prevalence of drug resistant tuberculosis (TB). A cohort of 233 culture positive TB patients was followed through smear microscopy, culture, drug susceptibility testing and DNA fingerprinting at baseline, after 3 months and at the end of treatment. Overall 172 patients (74%) became culture negative, while 43 (18%) remained positive at the end of treatment. Among those 43 cases, 58% of failures were determined to be due to treatment with an inadequate drug regimen and 42% to either an initial mixed infection or re-infection while under treatment. Overall, drug resistance amplification during treatment occurred in 3.4% of the patient cohort. This study demonstrates that treatment failure is linked to initial drug resistance, that amplification of drug resistance occurs, and that mixed infection and re-infection during standard treatment contribute to treatment failure in confined settings with high prevalence of drug resistance.
[Show abstract][Hide abstract] ABSTRACT: 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).
To measure the costs of intensified case finding (ICF) and isoniazid preventive therapy (IPT) services for HIV-infected patients in Battambang Province, Cambodia.
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.
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.
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.
Full-text · Article · Jul 2009 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: 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.
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%.
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.
No preview · Article · Mar 2009 · The International Journal of Tuberculosis and Lung Disease
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Feb 2009 · The Southeast Asian journal of tropical medicine and public health
[Show abstract][Hide abstract] ABSTRACT: Frank Cobelens and colleagues outline key research questions that need to be addressed to maximize the impact of programmatic management of drug-resistant tuberculosis.