Background Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated. Methods and Findings From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrolment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0–53.4) and HIV-uninfected (14.7; 4.1–52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0–18.8) and Karnofsky score <70 (2.1; 1.1–4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1–10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0–3.5). Conclusions The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients. Please see later in the article for the Editors' Summary
References
[1]
Mak A, Thomas A, Del Granado M, Zaleskis R, Mouzafarova N, et al. (2008) Influence of multidrug resistance on tuberculosis treatment outcomes with standardized regimens. Am J Respir Crit Care Med 178: 306–312.
[2]
World Health Organization (2009) Global tuberculosis control - a short update to the 2009 report. Geneva: World Health Organization.
[3]
Menzies D, Benedetti A, Paydar A, Royce S, Pai M, et al. (2009) Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med 6: e1000150. doi:10.1371/journal.pmed.1000150.
[4]
Rouillon A (1991) The Mutual Assistance Programme of the IUATLD. Development, contribution and significance. Bull Int Union Tuberc Lung Dis 66: 159–172.
[5]
World Health Organization (2009) Treatment of tuberculosis: guidelines – 4th edition. Geneva: World Health Organization.
[6]
World Health Organization (2006) Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization.
[7]
Espinal MA (2003) Time to abandon the standard retreatment regimen with first-line drugs for failures of standard treatment. Int J Tuberc Lung Dis 7: 607–608.
[8]
Matthys F, Rigouts L, Sizaire V, Vezhnina N, Lecoq M, et al. (2009) Outcomes after chemotherapy with WHO category II regimen in a population with high prevalence of drug resistant tuberculosis. PLoS One 4: e7954. doi:10.1371/journal.pone.0007954.
[9]
Quy HT, Lan NT, Borgdorff MW, Grosset J, Linh PD, et al. (2003) Drug resistance among failure and relapse cases of tuberculosis: is the standard re-treatment regimen adequate? Int J Tuberc Lung Dis 7: 631–636.
[10]
Cavalcante SC, Soares EC, Pacheco AG, Chaisson RE, Durovni B (2007) Community DOT for tuberculosis in a Brazilian favela: comparison with a clinic model. Int J Tuberc Lung Dis 11: 544–549.
[11]
Churchyard GJ, Corbett EL, Kleinschmidt I, Mulder D, De Cock KM (2000) Drug-resistant tuberculosis in South African gold miners: incidence and associated factors. Int J Tuberc Lung Dis 4: 433–440.
[12]
Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, et al. (2000) Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 283: 2537–2545.
[13]
Kimerling ME, Kluge H, Vezhnina N, Iacovazzi T, Demeulenaere T, et al. (1999) Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 3: 451–453.
[14]
Kironde S, Meintjies M (2002) Tuberculosis treatment delivery in high burden settings: does patient choice of supervision matter? Int J Tuberc Lung Dis 6: 599–608.
[15]
Ottmani SE, Zignol M, Bencheikh N, Laasri L, Chaouki N, et al. (2006) Results of cohort analysis by category of tuberculosis retreatment cases in Morocco from 1996 to 2003. Int J Tuberc Lung Dis 10: 1367–1372.
[16]
Pardeshi GS, Deshmukh D (2007) A comparison of treatment outcome in re-treatment versus new smear positive cases of tuberculosis under RNTCP. Indian J Public Health 51: 237–239.
[17]
Salaniponi FM, Nyirenda TE, Kemp JR, Squire SB, Godfrey-Faussett P, et al. (2003) Characteristics, management and outcome of patients with recurrent tuberculosis under routine programme conditions in Malawi. Int J Tuberc Lung Dis 7: 948–952.
[18]
Santha T, Garg R, Frieden TR, Chandrasekaran V, Subramani R, et al. (2002) Risk factors associated with default, failure and death among tuberculosis patients treated in a DOTS programme in Tiruvallur District, South India, 2000. Int J Tuberc Lung Dis 6: 780–788.
[19]
Saravia JC, Appleton SC, Rich ML, Sarria M, Bayona J, et al. (2005) Retreatment management strategies when first-line tuberculosis therapy fails. Int J Tuberc Lung Dis 9: 421–429.
[20]
Schreiber YS, Herrera AF, Wilson D, Wallengren K, Draper R, et al. (2009) Tuberculosis retreatment category predicts resistance in hospitalized retreatment patients in a high HIV prevalence area. Int J Tuberc Lung Dis 13: 1274–1280.
[21]
Sevim T, Atac G, Gungor G, Torun I, Aksoy E, et al. (2002) Treatment outcome of relapse and defaulter pulmonary tuberculosis patients. Int J Tuberc Lung Dis 6: 320–325.
[22]
Toungoussova OS, Nizovtseva NI, Mariandyshev AO, Caugant DA, Sandven P, et al. (2004) Impact of drug-resistant Mycobacterium tuberculosis on treatment outcome of culture-positive cases of tuberculosis in the Archangel oblast, Russia, in 1999. Eur J Clin Microbiol Infect Dis 23: 174–179.
[23]
Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, et al. (2006) Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS Med 3: e384. doi:10.1371/journal.pmed.0030384.
[24]
Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, et al. (2007) HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis 196: Suppl 1S86–S107.
[25]
Ministry of Health (2003) Uganda national antiretroviral treatment and care guidelines for adults and children. 1st edition. Kampala, Uganda: Ministry of Health.
[26]
(2000) diagnostic standards and classification of tuberculosis in adults and children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 161: 1376–1395.
[27]
(1996) Bactec 460 system: product and procedure manual. Sparks (Maryland): Becton, Dickenson, and Company.
[28]
(1999) Bactec MGIT 960 system user's manual. Sparks (Maryland): Becton, Dickenson, and Company.
[29]
Muhumuza J, Asiimwe BB, Kayes S, Mugyenyi R, Whalen C, et al. (2006) Introduction of an in-house PCR for routine identification of M. tuberculosis in a low-income country. Int J Tuberc Lung Dis 10: 1262–1267.
[30]
World Health Organization (2004) Rapid HIV tests: guidelines for use in HIV testing and counselling services in resource-constrained settings. Geneva: World Health Organization.
[31]
Greenland S (2008) Chapter 21: introduction to regression modeling. In: Rothman KJ, Greenland S, Lash TL, editors. Modern epidemiology. 3rd edition. Baltimore: Lippincott, Williams, and Wilkins.
[32]
Royston P, Ambler G, Sauerbrei W (1999) The use of fractional polynomials to model continuous risk variables in epidemiology. Int J Epidemiol 28: 964–974.
[33]
Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81: 515–526.
[34]
Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, et al. (2010) Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 362: 697–706.
[35]
Laserson KF, Thorpe LE, Leimane V, Weyer K, Mitnick CD, et al. (2005) Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 9: 640–645.
[36]
Temple B, Ayakaka I, Ogwang S, Nabanjja H, Kayes S, et al. (2008) Rate and amplification of drug resistance among previously-treated patients with tuberculosis in Kampala, Uganda. Clin Infect Dis 47: 1126–1134.
[37]
Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, et al. (2006) Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368: 1575–1580.
[38]
Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, et al. (2010) HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med 181: 80–86.
[39]
Pelly T, Moore DA, Gilman R, Evans C (2004) Recent tuberculosis advances in Latin America. Curr Opin Infect Dis 17: 397–403.
[40]
Keshavjee S, Farmer PE (2010) Picking up the pace–scale-up of MDR tuberculosis treatment programs. N Engl J Med 363: 1781–1784.
[41]
Small PM, Pai M (2010) Tuberculosis diagnosis–time for a game change. N Engl J Med 363: 1070–1071.
[42]
Espinal M, Raviglione MC (2008) From threat to reality: the real face of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 178: 216–217.
