High Multidrug-resistant Tuberculosis Research Articles

First national survey of anti-tuberculosis drug resistance in Azerbaijan and risk factors analysis.

Civilian population of the Republic of Azerbaijan. To determine patterns of anti-tuberculosis drug resistance among new and previously treated pulmonary tuberculosis (TB) cases, and explore their association with socio-demographic and clinical characteristics. National cross-sectional survey conducted in 2012-2013. Of 789 patients (549 new and 240 previously treated) who met the enrolment criteria, 231 (42%) new and 146 (61%) previously treated patients were resistant to any anti-tuberculosis drug; 72 (13%) new and 66 (28%) previously treated patients had multidrug-resistant TB (MDR-TB). Among MDR-TB cases, 38% of new and 46% of previously treated cases had pre-extensively drug-resistant TB (pre-XDR-TB) or XDR-TB. In previously treated cases, 51% of those who had failed treatment had MDR-TB, which was 15 times higher than in relapse cases (OR 15.2, 95%CI 6-39). The only characteristic significantly associated with MDR-TB was a history of previous treatment (OR 3.1, 95%CI 2.1-4.7); for this group, history of incarceration was an additional risk factor for MDR-TB (OR 2.8, 95%CI 1.1-7.4). Azerbaijan remains a high MDR-TB burden country. There is a need to implement countrywide control and innovative measures to accelerate early diagnosis of drug resistance in individual patients, improve treatment adherence and strengthen routine surveillance of drug resistance.

Pseudo R<SUP>2</SUP> Probablity Measures, Durbin Watson Diagnostic Statistics and Einstein Summations for Deriving Unbiased Frequentistic Inferences and Geoparameterizing Non-Zero First-Order Lag Autocorvariate Error in Regressed Multi-Drug Resistant Tuberculosis Time Series Estimators

In randomized clinical trials using clustered multi-drug resistant tuberculosis (MDR-TB) data, groups of human population are routinely assigned to treatments; whereas, observations are taken on the individual subjects using clinically-oriented explanatory covariate coefficient estimates for identifying sites of hyperendemic transmission. Further, standard methods for data analyses of clinical MDR-TB data postulate models relating observational parameters to the response variables without accurately quantitating varying observational intra-cluster error coefficient effects. Implicit in this assumption is that the effect of these error coefficient estimates are identical. However, non-differentiation of varying and constant residual within-cluster covariate coefficient uncertainty effects in a time-series clinical MDR-TB endemic transmission model can lead to misspecified forecasted predictors of endemic transmission zones (e.g., mesoendemic). In this research we constructed multiple georeferenced autoregressive hierarchical models accompanied by non-generalized predictive residual uncertainty non-normal diagnostic tests employing multiple covariate coefficient estimates clinically-sampled in San Juan de Lurigancho Lima, Peru. Initially, a SAS-based hierarchical agglomerative polythetic clustering algorithm was employed to determine high and low MDR-TB clusters stratified by prevalence data. Univariate statistics and Poisson regression models were then generated in R and PROC NL MIXED, respectively. Durbin-Watson statistics were derived. A Bayesian probabilistic estimation matrix was then constructed employing normal priors for each of the error coefficient estimates which revealed both spatially structured (SSRE) and spatially unstructured effects (SURE). The residuals in the high MDR-TB explanatory prevalent cluster revealed two major uncertainty estimate interactions: 1) as the number of bedrooms in a house in which infected persons resided increased and the percentage of isoniazid-sensitive infected persons increased, the standardized rate of tuberculosis tended to decrease; and, (2) as the average working time and the percentage of streptomycin-sensitive persons increased, the standardized rate of MDR-TB tended to increase. In the low MDR-TB explanatory time series cluster single marital status and building material used for house construction were important predictors. Latent explanatory non-normal error probabilities in empirically regressed MDR-TB clinical-sampled covariate estimates can be robustly spatiotemporally quantitated employing a first-order autoregressive resdiualized model and a Bayesian diagnostic uncertainty estimation matrix.

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India

BackgroundAdverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients.MethodsThis was a prospective, observational cohort study, using routine laboratory data in a Médecins Sans Frontières (MSF) clinic in collaboration with Sewri TB Hospital, Mumbai, India. Hypothyroidism was defined as a thyroid stimulating hormone (TSH) result >10 mIU/L at least once during treatment. Patients having a baseline result and one additional result after 3 months were eligible for enrolment.ResultsBetween October 2006 and March 2013, 116 patients were enrolled, 69 of whom were included. The median (IQR) age was 38 years (34-43) and 61% were male. By March 2013, 37/69 (54%) had hypothyroidism after at least 90 days of treatment. Age, gender, CD4 counts and stavudine-based ART were not associated with the occurrence of hypothyroidism in multivariate models. The co-administration of PAS and ethionamide was found to double the risk of hypothyroidism (RR: 1.93, 95% CI: 1.06-3.54).DiscussionHigh rate of hypothyroidism was recorded in a Mumbai cohort of MDR-TB/HIV co-infected patients on treatment. This is a treatable and reversible AE, however, it may go undiagnosed in the absence of regular monitoring. Care providers should not wait for clinical symptoms, as this risks compromising treatment adherence. Simple, affordable and reliable point-of-care tools for measuring TSH are needed, especially in high MDR-TB burden countries. Our findings suggest the need for TSH screening at baseline, three months, six months, and every six months thereafter for HIV-infected patients on MDR-TB treatment regimens containing PAS and/or ethionamide, until newer, safer and more efficacious MDR-TB regimens become available.

Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test

Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.

Risk factors and timing of default from treatment for non-multidrug-resistant tuberculosis in Moldova

The Republic of Moldova, in Eastern Europe, has among the highest reported nationwide proportions of tuberculosis (TB) patients with multidrug-resistant tuberculosis (MDR-TB) worldwide. Default has been associated with increased mortality and amplification of drug resistance, and may contribute to the high MDR-TB rates in Moldova. To assess risk factors and timing of default from treatment for non-MDR-TB from 2007 to 2010. A retrospective analysis of routine surveillance data on all non-MDR-TB patients reported. A total of 14.7% of non-MDR-TB patients defaulted from treatment during the study period. Independent risk factors for default included sociodemographic factors, such as homelessness, living alone, less formal education and spending substantial time outside Moldova in the year prior to diagnosis; and health-related factors such as human immunodeficiency virus co-infection, greater lung pathology and increasing TB drug resistance. Anti-tuberculosis treatment is usually initiated within an institutional setting in Moldova, and the default risk was highest in the month following the phase of hospitalized treatment (among civilians) and after leaving prison (among those diagnosed while incarcerated). Targeted interventions to increase treatment adherence for patients at highest risk of default, and improving the continuity of care for patients transitioning from institutional to community care may substantially reduce risk of default.

Assessing spatial heterogeneity of multidrug-resistant tuberculosis in a high-burden country

Multidrug-resistant tuberculosis (MDR-TB) is a major concern in countries of the former Soviet Union. The reported risk of resistance among tuberculosis (TB) cases in the Republic of Moldova is among the highest in the world. We aimed to produce high-resolution spatial maps of MDR-TB risk and burden in this setting. We analysed national TB surveillance data collected between 2007 and 2010 in Moldova. High drug susceptibility testing coverage and detailed location data permitted identification of subregional areas of higher MDR-TB risk. We investigated whether the distribution of cases with MDR-TB risk factors could explain this observed spatial variation in MDR-TB. 3447 MDR-TB cases were notified during this period; 24% of new and 62% of previously treated patients had MDR-TB. Nationally, the estimated annual MDR-TB incidence was 54 cases per 100 000 persons and >1000 cases per 100 000 persons within penitentiaries. We identified substantial geographical variation in MDR-TB burden and hotspots of MDR-TB. Locations with a higher percentage of previously incarcerated TB cases were at greater risk of being MDR-TB hotspots. Spatial analyses revealed striking geographical heterogeneity of MDR-TB. Methods to identify locations of high MDR-TB risk and burden should allow for better resource allocation and more appropriate targeting of studies to understand local mechanisms driving resistance.

Drug resistance-related mutations in multidrug-resistant Mycobacterium tuberculosis isolates from diverse geographical regions

BackgroundDrug resistance in Mycobacterium tuberculosis is associated with chromosomal mutations in selected genes. These mutations can be screened for an early warning system for drug-resistant tuberculosis. The prevalence of individual mutations differs geographically, which must be considered in developing globally applicable screening tests. MethodsIn order to analyse the geographical distribution and frequency of mutations conferring resistance to rifampicin, isoniazid and fluoroquinolones, the researchers investigated the presence of mutations in the rpoB gene, the katG gene, the mabA-inhA promoter region and the gyrA gene in clinical isolates of multidrug-resistant tuberculosis (MDR-TB) from Belarus, China, Iran/Iraq, Honduras, Romania and Uganda. For each study site, the researchers described the distribution of specific mutations in 20 clinical MDR-isolates. ResultsThe distribution of resistance-related mutations varied significantly between the study sites. Settings with a high incidence of MDR-TB, such as Belarus, showed a narrower spectrum of mutations related to rifampicin and isoniazid resistance and also a higher prevalence of fluoroquinolone resistance than study sites with a lower MDR-TB prevalence. ConclusionThis study confirms that there are significant geographical differences in the distribution of resistance-related mutations and suggests that an increased understanding of such differences in the specific distribution of resistance conferring mutations is crucial for development of new, generally applicable, molecular tools for rapid diagnosis of drug-resistant TB. The fact that a narrower distribution of mutations in high MDR-TB prevalence settings was seen suggests that much of the problems in these settings can be a result of an ongoing transmission of certain MDR-TB strains.

Availability of anti-tuberculosis drugs in Europe: Table 1–

To the Editors: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) represents a major threat to TB control globally and, specifically, in Europe [1–3]. MDR-/XDR-TB is at large due to clinical mismanagement of drug-susceptible and drug-resistant TB cases as well as to transmission of resistant strains [1–3]. Continuous availability of quality-controlled drugs is a prerequisite to ensure correct clinical management of TB patients [2, 4]. Comprehensive and updated information on the availability and registration procedures of first-line (FLD) and second-line (SLD) anti-TB drugs is not available, neither in Europe nor elsewhere. Anecdotal evidence suggested that in most European Union (EU) countries, where TB has a low incidence, procurement procedures are decentralised (not through Global Drug Facility, GDF), and with no specific responsibility for TB drug procurement available at the ministerial level. Despite high costs of SLD, registration procedures are strong enough to potentially prevent marketing and prescription of poor quality drugs. FLD and SLD are usually available (with mechanisms to prevent stock-outs), although the low number of drug doses sold can create challenges in assuring their continuous availability [5]. In EU countries with TB incidence >20 per 100,000 people, high MDR-TB prevalence and intermediate income, drug-procurement procedures are centralised (through GDF), drug costs are lower, and FLD (but not necessarily all SLD) are available. In these countries procurement relies on the Green Light Committee mechanism (GLC, a technical body from the World Health Organization (WHO) and partners providing assistance for developing national …

The dragon and the tiger: realties in the control of tuberculosis.

India and China are two Asian super-powers with developing economies carried on the shoulders of their booming populations. This growth can only be sustained by nurturing their “human resource”. However increasing reports of insufficient public health (PH) initiatives in India when compared to the aggressive PH system of China may prove to be the Achilles' heels for India. This review compares the PH system in India and China for combating Tuberculosis (TB), the disease responsible for maximum mortality and morbidity by a single infectious agent. While China has acknowledged the disease load and thereafter has methodically improved its reporting, detection, diagnosis and treatment, India is still in denial of the imminent health risk. The Indian PH system still considers TB as a “facultative” disease for which the required control measures are already in place and functioning. Globally, India and China recorded the highest Multi-Drug Resistant TB (MDR) cases notified in 2010 (64000 and 63000, respectively). Additionally non-government sources reported extremely high proportions of MDR in India. Here we have compared the medical, social and economic approaches of the two nations towards better management and control of TB. Does India have lessons to learn from China?

An Integrated Approach to Rapid Diagnosis of Tuberculosis and Multidrug Resistance Using Liquid Culture and Molecular Methods in Russia

ObjectiveTo analyse the feasibility, cost and performance of rapid tuberculosis (TB) molecular and culture systems, in a high multidrug-resistant TB (MDR TB) middle-income region (Samara, Russia) and provide evidence for WHO policy change.MethodsPerformance and cost evaluation was conducted to compare the BACTEC™ MGIT™ 960 system for culture and drug susceptibility testing (DST) and molecular systems for TB diagnosis, resistance to isoniazid and rifampin, and MDR TB identification compared to conventional Lowenstein-Jensen culture assays.Findings698 consecutive patients (2487 sputum samples) with risk factors for drug-resistant tuberculosis were recruited. Overall M. tuberculosis complex culture positivity rates were 31.6% (787/2487) in MGIT and 27.1% (675/2487) in LJ (90.5% and 83.2% for smear-positive specimens). In total, 809 cultures of M. tuberculosis complex were isolated by any method. Median time to detection was 14 days for MGIT and 36 days for LJ (10 and 33 days for smear positive specimens) and indirect DST in MGIT took 9 days compared to 21 days on LJ. There was good concordance between DST on LJ and MGIT (96.8% for rifampin and 95.6% for isoniazid). Both molecular hybridization assay results correlated well with MGIT DST results, although molecular assays generally yielded higher rates of resistance (by approximately 3% for both isoniazid and rifampin).ConclusionWith effective planning and logistics, the MGIT 960 and molecular based methodologies can be successfully introduced into a reference laboratory setting in a middle incidence country. High rates of MDR TB in the Russian Federation make the introduction of such assays particularly useful.

Multidrug- and extensively drug-resistant TB in persons living with HIV

Multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) represent an emerging public health problem worldwide. The collision of the HIV epidemic with MDR- and XDR-TB has produced disastrous consequences for individual patients, with very high mortality rates reported in outbreaks among HIV-infected individuals. There is evidence of the importance of primary resistance among HIV-infected persons with XDR-TB, while the relevance of acquired resistance during inappropriate treatment among HIV-infected persons is uncertain, and TB case management of HIV-infected and -uninfected persons is based on similar standard practices to ensure treatment adherence. Current data show a limited geographical overlap of the XDR-TB and HIV epidemics: such data must be interpreted cautiously owing to the lack of adequate testing for both conditions. In fact, there are signs of an evolving epidemiological situation characterized by increased outbreak risk in concentrated areas owing to the extension of the HIV epidemic into areas of high MDR-TB prevalence and of the MDR-TB epidemic into areas of high HIV prevalence. There is a paucity of studies on treatment outcome among HIV-infected XDR-TB patients, and the only available report shows extremely high mortality rate and very short survival. Rapid diagnosis of TB and MDR-TB will be pivotal to reduce mortality among persons co-infected with HIV. However, while rapid diagnosis of MDR-TB is feasible with molecular assays on direct specimens, molecular approaches are still insensitive for XDR-TB diagnosis. There is speculative evidence that effective strategies for early HIV diagnosis and treatment will play a role in limiting the spread, and possibly improving the outcome of XDR-TB. Prevention is currently the mainstay of XDR-TB control in HIV communities. Strategies for infection control based on administrative procedures, environmental control and respiratory protection should be a priority for countries where both XDR-TB and HIV are prevalent. However, only the comprehensive implementation of the full Stop TB Strategy may be expected to curb the devastating impact of XDR-TB on HIV-infected persons.

Prevalence of tuberculosis drug resistance in 10 provinces of China

BackgroundThe emergence of drug-resistant tuberculosis (TB) hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB) patients in 1996–2004 to assess levels of drug resistance.MethodsProvincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST) against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6%) was re-tested by the national reference laboratory (NRL).ResultsOf 14,059 patients tested 11,052 (79%) were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB) among all cases was 9.3% (range 2.2%–10.4%); 5.4% (range 2.1% – 10.4%) among new cases and 25.6% (range 11.7%–36.9%) among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients.ConclusionMDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings.

Rapid diagnosis of drug-resistant TB using line probe assays: from evidence to policy

Growing concerns about the spread of multidrug-resistant tuberculosis (MDR-TB) and the emergence of extensively drug-resistant TB have triggered substantial interest in the development and application of rapid tests for the detection of drug-resistant TB. Molecular assays to detect gene mutations that signal drug resistance are widely recognized as being most suited for rapid diagnosis. Among molecular assays, line probe assays have shown great promise. Currently, two line probe assays are commercially available: the INNO-LiPA® Rif. TB kit (Innogenetics NV, Gent, Belgium) and the GenoType® MTBDRplus assay (Hain Lifescience GmbH, Nehren, Germany). Evidence from a systematic review suggests that INNO-LiPA is a highly sensitive and specific test for the detection of rifampicin resistance in culture isolates. The test, however, appeared to have relatively lower sensitivity when used directly on clinical specimens. Another meta-analysis showed that the GenoType MTBDR assays had excellent accuracy for rifampicin resistance, even when used directly on clinical specimens. While specificity was excellent for isoniazid, sensitivity estimates were modest and variable. Based on evidence and expert opinion, the WHO recently endorsed the use of molecular line probe assays for rapid screening of patients at risk of MDR-TB. Special initiatives have been announced to make these assays accessible and affordable for countries with high MDR-TB prevalence. With strong evidence and new policy directives, the stage is now set for the use of rapid tests for MDR-TB diagnosis. Whether molecular tools, such as line probe assays, will actually make a clinical and public-health impact remains to be determined.

High coverage with HAART is required to substantially reduce the number of deaths from tuberculosis: system dynamics simulation

We used a system dynamics simulation model of the transmission dynamics of drug-sensitive tuberculosis (DSTB), multidrug-resistant tuberculosis (MDRTB) and HIV to estimate the impact of coverage with highly active antiretroviral therapy (HAART) and different cure rates for MDRTB in settings of explosive HIV epidemics and high MDRTB levels. Population coverage levels at 0%, 25%, 50%, 75% and 100% for HAART, and 5% and 80% of MDRTB treatment cure rates were simulated over a 10-year period and cumulative deaths from tuberculosis and HIV-associated tuberculosis were estimated for populations with latent tuberculosis, DSTB, MDRTB, HIV and HIV-associated tuberculosis. Depending on levels of HAART population coverage, increasing MDRTB cure rates from 5% to 80% reduces cumulative tuberculosis deaths by 1% and 13%. High population coverage with HAART (75% or higher), allied with high MDRTB cure rates, reduces cumulative deaths by 60%, with limited impact below this level. High coverage with HAART is required to substantially reduce the number of deaths from tuberculosis.

Impact of joined-up HIV harm reduction and multidrug resistant tuberculosis control programmes in Estonia: System dynamics simulation model

In Eastern Europe and Central Asia (ECA) the control of tuberculosis, multidrug resistant tuberculosis (MDRTB) and human immunodeficiency virus (HIV) poses important public health challenges. We used system dynamics simulation to determine impact on cumulative HIV/AIDS, tuberculosis and HIV-associated-tuberculosis deaths, over 20 years, of harm-reduction programmes to reduce needle-sharing and injection-frequency amongst injecting drug users (IDUs) and multidrug resistant tuberculosis (MDRTB) control in a population with an explosive HIV epidemic in IDUs and high MDRTB prevalence. We estimate that the number of HIV-associated-deaths will decline by 30% with effective harm-reduction programmes but double if these are ineffective. In our model, effective MDRTB and HIV control reduces cumulative tuberculosis deaths by 54%, cumulative MDRTB deaths 15-fold and cumulative HIV-associated-tuberculosis-deaths 2-fold. Effective MDRTB control, without effective harm-reduction programmes, only reduce tuberculosis deaths by 22%. However, effective harm-reduction programme with a poor MDRTB control reduce cumulative tuberculosis deaths by 34%, MDRTB by 14% and HIV-associated-tuberculosis by 56%. Even with good control programmes for drug sensitive TB, neglecting harm reduction and MDRTB control will result in 50% more tuberculosis-related deaths than if both are effectively addressed. Effective harm-reduction programmes reduces cumulative deaths from tuberculosis more substantively than effective MDRTB control. Our finding have important policy implications for communicable disease policies in post-Soviet countries, which need to substantially change if they are to effectively address the emerging HIV and MDRTB epidemics.

Rapid Detection of Ofloxacin Resistance in Mycobacterium tuberculosis by Two Low-Cost Colorimetric Methods: Resazurin and Nitrate Reductase Assays

We have evaluated the performance of two rapid, low-cost methods for the detection of ofloxacin (OFX) resistance with 95 Mycobacterium tuberculosis isolates from countries with high multidrug-resistant tuberculosis endemicity. Results obtained by nitrate reductase and resazurin assays showed 100% agreement with those of the proportion method on 7H11 agar using 2 mug of OFX/ml. We confirmed the resistance of all isolates found to be resistant to OFX by the Mycobacterium Growth Indicator Tube system, and complete agreement among all methods was observed. Nitrate reductase and resazurin assays are rapid, simple, low-cost methods and might become inexpensive alternative procedures for rapid detection of OFX resistance in low-resource countries.