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      Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review


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          The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data.

          Methodology and Principal Findings

          To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis.


          Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

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          The competitive cost of antibiotic resistance in Mycobacterium tuberculosis.

          Mathematical models predict that the future of the multidrug-resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. We show that in laboratory-derived mutants of Mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic background. In contrast, we demonstrate that prolonged patient treatment can result in multidrug-resistant strains with no fitness defect and that strains with low- or no-cost resistance mutations are also the most frequent among clinical isolates.
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            HIV infection and multidrug-resistant tuberculosis: the perfect storm.

            Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global epidemic, with ~425,000 new cases estimated to occur annually. The global human immunodeficiency virus (HIV) infection epidemic has caused explosive increases in TB incidence and may be contributing to increases in MDR-TB prevalence. We reviewed published studies and available surveillance data evaluating links between HIV infection and MDR-TB to quantify convergence of these 2 epidemics, evaluate the consequences, and determine essential steps to address these epidemics. Institutional outbreaks of MDR-TB have primarily affected HIV-infected persons. Delayed diagnosis, inadequate initial treatment, and prolonged infectiousness led to extraordinary attack rates and case-fatality rates among HIV-infected persons. Whether this sequence occurs in communities is less clear. MDR-TB appears not to cause infection or disease more readily than drug-susceptible TB in HIV-infected persons. HIV infection may lead to malabsorption of anti-TB drugs and acquired rifamycin resistance. HIV-infected patients with MDR-TB have unacceptably high mortality; both antiretroviral and antimycobacterial treatment are necessary. Simultaneous treatment requires 6-10 different drugs. In HIV-prevalent countries, TB programs struggle with increased caseloads, which increase the risk of acquired MDR-TB. Surveillance data suggest that HIV infection and MDR-TB may converge in several countries. Institutional outbreaks, overwhelmed public health programs, and complex clinical management issues may contribute to the convergence of the MDR-TB and HIV infection epidemics. To forestall disastrous consequences, infection control, rapid case detection, effective treatment, and expanded program capacity are needed urgently.
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              Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries.

              No large-scale study has investigated the impact of multidrug-resistant tuberculosis (TB) on the outcome of standard short-course chemotherapy under routine countrywide TB control program conditions in the World Health Organization's (WHO) directly observed treatment short-course strategy for TB control. To assess the results of treatment with first-line drugs for patients enrolled in the WHO and the International Union Against Tuberculosis and Lung Disease's global project on drug-resistance surveillance. Retrospective cohort study of patients with TB in the Dominican Republic, Hong Kong Special Administrative Region (People's Republic of China), Italy, Ivanovo Oblast (Russian Federation), the Republic of Korea, and Peru. New and retreatment TB cases who received short-course chemotherapy with isoniazid, rifampicin, pyrazinamide, and either ethambutol or streptomycin between 1994 and 1996. Treatment response according to WHO treatment outcome categories (cured; died; completed, defaulted, or failed treatment; or transferred). Of the 6402 culture-positive TB cases evaluated, 5526 (86%) were new cases and 876 (14%) were retreatment cases. A total of 1148 (20.8%) new cases and 390 (44.5%) retreatment cases were drug resistant, including 184 and 169 cases of multidrug-resistant TB, respectively. Of the new cases 4585 (83%) were treated successfully, 138 (2%) died, and 151 (3%) experienced short-course chemotherapy failure. Overall, treatment failure (relative risk [RR], 15.4; 95% confidence interval [CI], 10.6-22.4; P<.001) and mortality (RR, 3.73; 95% CI, 2.13-6.53; P<.001) were higher among new multidrug-resistant TB cases than among new susceptible cases. Even in settings using 100% direct observation, cases with multidrug resistance had a significantly higher failure rate than those who were susceptible (9/94 [10%] vs 8/1410 [0.7%]; RR, 16.9; 95% CI, 6.6-42.7; P<.001). Treatment failure was also higher among patients with any rifampicin resistance (n=115) other than multidrug resistance (RR, 5.48; 95% CI, 3.04-9.87; P<.001), any isoniazid resistance (n=457) other than multidrug resistance (RR, 3. 06; 95% CI, 1.85-5.05; P<.001), and among patients with TB resistant to rifampicin only (n=76) (RR, 5.47; 95% CI, 2.68-11.2; P<.001). Of the retreatment cases, 497 (57%) were treated successfully, 51 (6%) died, and 124 (14%) failed short-course chemotherapy treatment. Failure rates among retreatment cases were higher in those with multidrug-resistant TB, with any isoniazid resistance other than multidrug resistance, and in cases with TB resistant to isoniazid only. These data suggest that standard short-course chemotherapy, based on first-line drugs, is an inadequate treatment for some patients with drug-resistant TB. Although the directly observed treatment short-course strategy is the basis of good TB control, the strategy should be modified in some settings to identify drug-resistant cases sooner, and to make use of second-line drugs in appropriate treatment regimens. JAMA. 2000;283:2537-2545

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                4 April 2011
                : 6
                : 4
                : e17601
                [1 ]KNCV Tuberculosis Foundation, The Hague, The Netherlands
                [2 ]Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
                [3 ]Cluster Infectious Disease Control, Municipal Health Service (GGD) Amsterdam, Amsterdam, The Netherlands
                [4 ]South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa
                [5 ]Department of Community Medicine, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
                McGill University, Canada
                Author notes

                Statistical/mathematical analysis after discussion with all authors (in particular BW and MW): NN. Conceived and designed the experiments: EWT MJvdW MB BW NN. Performed the experiments: EWT NN. Analyzed the data: EWT NN. Wrote the paper: NN EWT.

                Tiemersma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 4 November 2010
                : 2 February 2011
                Page count
                Pages: 13
                Research Article
                Population Biology
                Population Metrics
                Death Rate
                Clinical Research Design
                Observational Studies
                Systematic Reviews
                Infectious Disease Epidemiology
                Infectious Diseases
                Bacterial Diseases
                Multi-Drug-Resistant Tuberculosis
                Tropical Diseases (Non-Neglected)
                Public Health



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