Isoniazid Resistant and Multidrug-Resistant Tuberculosis Among Foreign-born^*,† Cases in Recent U.S. NTSS (2007–2009), Previous U.S. NTSS (1993–2006) and Global DRS (1994–2007) Data.

<p><b>Note.</b> Countries and regions are sorted in descending order by prevalence of MDR TB in recent U.S. NTSS data (2007–2009).</p><p>N = total number of patients from specific country or region with reported DST results.</p><p>n = total number of patients from specific country or region with reported pattern of resistance (INH resistant or MDR, respectively).</p><p>NTSS = National Tuberculosis Surveillance System.</p><p>Global DRS =  Global Project on Anti-Tuberculosis Drug Resistance Surveillance.</p>*<p>Foreign-born include persons born outside the United States, American Samoa, the Federated States of Micronesia, Guam, the Republic of the Marshall Islands, Midway Island, the Commonwealth of the Northern Mariana Islands, Puerto Rico, the Republic of Palau, the U.S. Virgin Islands, and U.S. minor and outlying Pacific islands.</p>†<p>TB cases from 14 countries for which prevalence of drug-resistant TB was reported separately were not included in respective WHO regions counts.</p>‡<p>Rank of country was assigned based on 5-year average number of TB cases from that country in the U.S. in 2005–2009. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049355#pone.0049355-CDC1" target="_blank">[1]</a>.</p>§<p>WHO nine epidemiological regions <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049355#pone.0049355-World3" target="_blank">[8]</a> include following countries:</p><p><b>Africa – high HIV:</b> Botswana, Burkina Faso, Burundi, Cameroon, Central African Rep, Chad, Congo, Côte d’Ivoire, DR Congo, Ethiopia, Equatorial Guinea, Gabon, Kenya, Lesotho, Malawi, Mozambique, Namibia, Nigeria, Rwanda, South Africa, Swaziland, Uganda, UR Tanzania, Zambia, Zimbabwe. Ethiopia was excluded from the region estimates and reported separately.</p><p><b>Africa – low HIV:</b> Algeria, Angola, Benin, Cape Verde, Comoros, Eritrea, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Madagascar, Mali, Mauritania, Mauritius, Niger, Sao Tome & Principe, Senegal, Seychelles, Sierra Leone, Togo.</p><p><b>Central Europe:</b> Albania, Bosnia & Herzegovina, Croatia, Cyprus, Hungary, Poland, Serbia & Montenegro, Slovakia, Slovenia, TFYR Macedonia, Turkey.</p><p><b>Eastern Europe:</b> Armenia, Azerbaijan, Belarus, Bulgaria, Estonia, Georgia, Kazakhstan, Kyrgystan, Latvia, Lithuania, Rep Moldova, Romania, Russian Federation, Tajikistan, Turkmenistan, Ukraine, Uzbekistan.</p><p><b>Eastern Mediterranean:</b> Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, Somalia, Sudan, Syrian Arab Rep, Tunisia, United Arab Emirates, West Bank & Gaza Strip, Yemen.</p><p><b>Established Market Economies</b>: Andorra, Australia, Austria, Belgium, Canada, Czech Rep, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Japan, Luxembourg, Malta, Monaco, Netherlands, New Zealand, Norway, Portugal, San Marino, Singapore, Spain, Sweden, Switzerland, Vatican City, United Kingdom.</p><p><b>Latin America:</b> Anguilla, Antigua & Barbuda, Argentina, Bahamas, Barbados, Belize, Bermuda, Bolivia, Brazil, British Virgin Is, Cayman Is, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Montserrat, Netherlands Antilles, Nicargua, Panama, Paraguay, Peru, St Kitts & Nevis, St Lucia, St Vincent & the Grenadines, Suriname, Trinidad & Tobago, Turks & Caicos Is, Uruguay, Venezuela. Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Mexico and Peru were excluded from the region estimates and reported separately.</p><p><b>South-East Asia:</b> Bangladesh, Bhutan, DPR Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, Timor-Leste. India was excluded from the region estimates and reported separately.</p><p><b>Western Pacific:</b> Brunei Darussalam, Cambodia, China, China Hong Kong SAR, China Macao SAR, Cook Is, Fiji, French Polynesia, Kiribati, Lao PDR, Malaysia, Mongolia, Nauru, New Caledonia, Niue, Papua New Guinea, Philippines, Rep Korea, Solomon Is, Taiwan, Tokelau, Tonga, Tuvalu, Vanuatu, Viet Nam, Wallis & Futuna Is, Western Samoa. Cambodia, China, Philippines, Republic of Korea and Viet Nam were excluded from the region estimates and reported separately.</p

Correlation and Simple Linear Regression Analyses of Prevalence of Drug-resistant TB in Recent and Previous U.S. NTSS Data and Global DRS Data.

<p>Note. *P value is reported for F test of overall significance of simple linear regression model. Dashes were put for comparisons where no linear association was observed. NTSS = National Tuberculosis Surveillance System. Global DRS =  Global Project on Anti-Tuberculosis Drug Resistance Surveillance.</p

Scatterplots of (A) prevalence of isoniazid resistance among recent foreign-born NTSS cases (2007–2009) versus prevalence of isoniazid resistance among (a) previous foreign-born NTSS cases (1993–2006), and (b) Global DRS TB cases (1994–2007), and (B) prevalence of MDR TB among foreign-born NTSS cases (2007–2009) versus prevalence of MDR TB among (c) previous foreign-born NTSS cases (1993–2006), and (d) Global DRS TB cases (1994–2007).

<p>Each dot represents a country or a region as specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049355#pone-0049355-t001" target="_blank">Table 1</a>.</p

Associations between <i>M. tuberculosis</i> complex lineage and acquired resistance to isoniazid, rifamycins, second-line injectables, and fluoroquinolones.

*<p>Adjusted for HIV status.</p>†<p>Adjusted for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy.</p><p>Abbreviations: CI = confidence interval, – = no prevalence ratio calculated because no cases had acquired resistance.</p

Independent predictors of acquired resistance to isoniazid and rifamycins in multivariable regression analysis.

<p>Abbreviation: CI = confidence interval, DST = drug susceptibility test, DOT = directly observed therapy.</p

Sociodemographic and clinical factors associated with acquired resistance to rifamycins (N = 4,005).

*<p>Regions defined by World Health Organization <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0083006#pone.0083006-World3" target="_blank">[37]</a>.</p><p>Missing values not reported in table.</p><p>Abbreviations: PR = prevalence ratio, CI = confidence interval, DST = drug susceptibility test, AFB = acid-fast bacilli, DOT = directly observed therapy.</p

Selection of cases included in analysis.

<p>Abbreviations: TB = tuberculosis, DST = drug susceptibility test, AR = acquired resistance.</p

Association between Regimen Composition and Treatment Response in Patients with Multidrug-Resistant Tuberculosis: A Prospective Cohort Study

<div><p>Background</p><p>For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.</p><p>Methods and Findings</p><p>We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph.</p><p>In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen).</p><p>The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial sputum culture conversion, not reversion or long-term relapse.</p><p>Conclusions</p><p>MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens.</p></div

Inclusion of patients in the analysis.

<p>MDR-TB is tuberculosis resistant to at least isoniazid and rifampin; XDR-TB is tuberculosis resistant to at least isoniazid, rifampin, one fluoroquinolone, and one second-line injectable drug.</p

Time to initial sputum culture conversion by average number of potentially effective drugs received per day.

<p>Initial sputum culture conversion was defined as at least two consecutive negative cultures of sputum samples collected at least 30 d apart.</p