Cox, H S; McDermid, C; Azevedo, V; Muller, O; Coetzee, D; Simpson, J; Barnard, M; Coetzee, G; van Cutsem, G; Goemaere, E

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MSF Field Research Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa. Authors Citation DOI Journal Rights Cox, H S; McDermid,
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MSF Field Research Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa. Authors Citation DOI Journal Rights Cox, H S; McDermid, C; Azevedo, V; Muller, O; Coetzee, D; Simpson, J; Barnard, M; Coetzee, G; van Cutsem, G; Goemaere, E Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa. 2010, 5 (11):e13901 PLoS ONE /journal.pone PloS One Published by Public Library of Science, [url]http://www.plosone.org/[/url] Archived on this site by Open Access permission Downloaded 23-Apr :00:56 Link to item Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa Helen S. Cox 1,2,3 *, Cheryl McDermid 2, Virginia Azevedo 4, Odelia Muller 2, David Coetzee 5, John Simpson 6, Marinus Barnard 6, Gerrit Coetzee 7, Gilles van Cutsem 2,5, Eric Goemaere 2,5 1 Burnet Institute, Melbourne, Australia, 2 Médecins Sans Frontières, Cape Town, South Africa, 3 Monash University, Melbourne, Australia, 4 City of Cape Town Health, Cape Town, South Africa, 5 University of Cape Town, Cape Town, South Africa, 6 National Health Laboratory Service, Cape Town, South Africa, 7 National Health Laboratory Service, Johannesburg, South Africa Abstract Background: Although multidrug-resistant tuberculosis (MDR-TB) is emerging as a significant threat to tuberculosis control in high HIV prevalence countries such as South Africa, limited data is available on the burden of drug resistant tuberculosis and any association with HIV in such settings. We conducted a community-based representative survey to assess the MDR- TB burden in Khayelitsha, an urban township in South Africa with high HIV and TB prevalence. Methodology/Principal Findings: A cross-sectional survey was conducted among adult clinic attendees suspected for pulmonary tuberculosis in two large primary care clinics, together constituting 50% of the tuberculosis burden in Khayelitsha. Drug susceptibility testing (DST) for isoniazid and rifampicin was conducted using a line probe assay on positive sputum cultures, and with culture-based DST for first and second-line drugs. Between May and November 2008, culture positive pulmonary tuberculosis was diagnosed in 271 new and 264 previously treated tuberculosis suspects (sample enriched with previously treated cases). Among those with known HIV status, 55% and 71% were HIV infected respectively. MDR-TB was diagnosed in 3.3% and 7.7% of new and previously treated cases. These figures equate to an estimated case notification rate for MDR-TB of 51/100,000/year, with new cases constituting 55% of the estimated MDR-TB burden. HIV infection was not significantly associated with rifampicin resistance in multivariate analyses. Conclusions/Significance: There is an extremely high burden of MDR-TB in this setting, most likely representing ongoing transmission. These data highlight the need to diagnose drug resistance among all TB cases, and for innovative models of case detection and treatment for MDR-TB, in order to interrupt transmission and control this emerging epidemic. Citation: Cox HS, McDermid C, Azevedo V, Muller O, Coetzee D, et al. (2010) Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa. PLoS ONE 5(11): e doi: /journal.pone Editor: Ben Marais, University of Stellenbosch, South Africa Received June 27, 2010; Accepted October 19, 2010; Published November 15, 2010 Copyright: ß 2010 Cox 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. Funding: This study was funded by Medecins Sans Frontieres, Belgium. The funders were involved in study design, data collection and analysis. However, final preparation of the manuscript and the decision to publish rests with the first author. Competing Interests: The authors have declared that no competing interests exist. * Introduction There are an estimated 13,000 cases of multidrug-resistant tuberculosis (MDR-TB) emerging in South Africa each year [1]. These estimates are primarily based on a national survey performed in 2001, combined with routinely reported case numbers, and thus many believe this to be an under-estimation of the current situation. In addition, South Africa has a growing epidemic of extensively drug-resistant tuberculosis (XDR-TB) associated with high mortality among HIV infected individuals [2]. The continued emergence of MDR- and XDR-TB poses a significant threat not only to tuberculosis control but also to progress made in the expanded provision of antiretroviral treatment (ART) for HIV. Drug-resistant tuberculosis (DR-TB) requires much longer and more costly treatment regimens than drug-susceptible tuberculosis, and in most high HIV prevalence settings, there is limited capacity for diagnosis. Thus, in many settings, few patients are diagnosed with DR-TB and even fewer receive adequate treatment. The HIV epidemic has driven dramatic increases in tuberculosis case notifications in southern Africa [3]. While expanding access to ART is expected to ultimately reduce tuberculosis case notifications, it may also contribute to the large pool of individuals with increased vulnerability to TB created by the HIV epidemic [4]. The convergence of these conditions: the high rate of tuberculosis prevalence, a vulnerable population and the existence of undiagnosed and untreated drug resistant tuberculosis create the potential for dramatically increasing epidemics. To date, there have been limited data available on the prevalence of DR-TB in high HIV prevalence settings. Only 12 countries in the African region have conducted nationwide surveys since 2000, with few disaggregating by HIV status [1]. While a number of countries are planning national representative surveys, such surveys aimed at deriving nationwide estimates of DR-TB PLoS ONE 1 November 2010 Volume 5 Issue 11 e13901 burden may mask pockets of extremely high tuberculosis drug resistance, particularly in settings with existing high rates of both HIV and tuberculosis. There is an urgent need to quantify the extent of the drug resistant tuberculosis epidemic in these settings in order to advocate for and develop strategies for control. This study aimed to assess the burden of tuberculosis drug resistance in a peri-urban setting in Khayelitsha Township outside Cape Town, South Africa. Methods Study setting Khayelitsha is a high population density township situated 30 km from Cape Town with a population estimated at more than 500,000. Poverty and unemployment are high and the majority live in informal housing. In 2006, the prevalence of HIV among antenatal clinic attendees was 33% and close to 6,000 tuberculosis cases were notified in 2008, giving an estimated case notification rate of 1158/100,000/year (based on an estimated population of 500,000) [5,6]. In response to increasing numbers of DR-TB cases seen in Khayelitsha clinics and poor patient outcomes, a pilot project to provide community-based care and treatment for DR- TB was initiated in 2007 [7]. The pilot project is implemented by Médecins Sans Frontières (MSF) in collaboration with the City of Cape Town and the Provincial Government of the Western Cape. Survey design A cross-sectional survey among clinic attendees suspected for pulmonary tuberculosis was conducted in two large primary care clinics in Khayelitsha between May and November These clinics combined account for 50% of the TB case burden in Khayelitsha. Clinic attendees, aged 18 years and over, not currently receiving TB treatment and in whom tuberculosis was suspected clinically, were eligible to participate. The study was explained by clinic staff and written informed consent was obtained from each participant. The study was approved by the University of Cape Town Ethical Review Committee and by both the City of Cape Town and the Western Cape Province Health Department. The desired sample size was determined separately for new and previously treated culture positive TB cases. Previous tuberculosis treatment was defined as 1 month or more of anti-tuberculosis treatment. Based on estimated proportions of MDR-TB of 2% and 4% respectively in South Africa [8], minimum sample sizes were 121 and 236 respectively (precision 2.5% and 5% alpha level). For logistical reasons and allowing for missing data, a target of 250 in each category was sought. Drug susceptibility testing Two sputum samples were collected one hour apart and were transported the same day to the National Health Laboratory Service (NHLS) TB laboratory in Cape Town as per routine practice. Fluorescence sputum smear microscopy was performed on both sputum specimens in accordance with guidelines from the International Union Against Tuberculosis and Lung Disease (IUATLD) [9]. One specimen was cultured using the BACTEC MGIT 960 system (BD Diagnostics Systems, Sparks, MD). Positive cultures were confirmed as Mycobacterium tuberculosis complex using Ziehl-Neelsen staining and p- nitrobenzoic acid testing [10]. Resistance to rifampicin and isoniazid was determined on positive cultures using a rapid line probe assay (LPA) (Hain GenoType MTBDRplus) as previously trialled in this laboratory [11]. All subcultures were later transported to the NHLS laboratory in Johannesburg for conventional culture-based drug susceptibility testing to rifampicin, isoniazid, ethambutol, pyrazinamide, streptomycin, ofloxacin, ethionamide and the second-line injectable agents (amikacin, kanamycin and capreomycin) also using the BACTEC MGIT 960 system. Two concentrations of isoniazid were tested, 0.1 and 0.4 mg/ml, to assess high and low level isoniazid resistance [12]. For rifampicin and isoniazid, drug resistance was defined as resistance shown on either the rapid LPA or the conventional culture based susceptibility test. For isoniazid, low level resistance was defined as resistant. Multidrug resistant tuberculosis (MDR-TB) is defined as resistance to both isoniazid and rifampicin and extensively drug resistant tuberculosis (XDR- TB) is defined as MDR-TB with additional resistance to a fluoroquinolone and a second-line injectable agent. Data collection and analysis Data on previous TB treatment, demographics, HIV status and antiretroviral treatment at the time of TB diagnosis were recorded routinely during the clinical assessment by a primary care nurse. Data on previous TB treatment was additionally verified among patients starting treatment through a medical record review. All data were entered on a database using Excel (Microsoft Office 2003). Data analysis, including multivariate logistic regression models, was conducted with SPSS (Release , 2008). To investigate factors potentially associated with rifampicin resistance, both univariate and multivariate logistic regression analyses were conducted. Previous TB treatment was classified as either: new (not previously treated), the most recent TB treatment episode in 2007/08 (the survey was conducted between May and November 2008) or the most recent treatment episode prior to Factors significant or approaching significance (p = 0.05) on univariate analysis were entered into the multivariate logistic regression models. Factors were coded as categorical variables with missing data included as a category. All factors were entered as a block into multivariate logistic regression models and goodness of fit was assessed with the Hosmer and Lemeshow statistic [13]. The MDR-TB burden in Khayelitsha was estimated by applying the proportions of MDR-TB found through the survey to the case notification data for the whole of Khayelitsha in 2008 [6]. Estimated MDR-TB incidence was then calculated using an estimated population for Khayelitsha of 500,000. An approximation of MDR-TB transmission was made based on the assumptions that DR-TB among new cases represents transmission rather than acquired drug resistance and that the same level of primary transmission is likely to occur among previously treated TB cases, given extensive reinfection in endemic settings. Results Culture positive tuberculosis During the study period, 1,842 (96%) of the 1,928 eligible clinic attendees suspected for pulmonary tuberculosis seen in the two clinics were recruited to the survey (Figure 1). Recruitment of participants not previously treated for tuberculosis ended in August 2008 as the desired sample size was estimated to have been reached. Recruitment of previously treated participants continued until November 2008, hence the overall combined sample does not reflect the relative proportions of new and previously treated TB suspects seen in the clinics. In TB suspects for whom valid culture results were obtained (including valid positive and negative cultures), culture positive tuberculosis was diagnosed in 271/732 (37%) cases among those not previously treated and 264/843 (31%) cases among those with more than one month of previous tuberculosis treatment (Figure 1). The most common reasons for not obtaining a valid culture were PLoS ONE 2 November 2010 Volume 5 Issue 11 e13901 Figure 1. Participant recruitment and culture-positive tuberculosis diagnosed among TB suspects. New TB suspects were recruited from May through August, while previously treated suspects were recruited May through November, * Valid culture results include negative and positive cultures and exclude contaminated cultures, those found to be non-tuberculous mycobacteria or those with no growth. doi: /journal.pone g001 contamination, non-tuberculosis mycobacteria and lost or leaked sputum samples. After investigation, 17 culture positive cases were excluded as the previous tuberculosis treatment status could not be determined (Figure 1). HIV status was known for 88% of new and 90% of previously treated cases (Table 1). The most common reason for unknown HIV status was refusal to be tested. Among new TB cases with known HIV status, 55% were HIV infected, while 71% of previously treated cases were HIV positive (p = 0.001). First-line anti-tuberculosis resistance Valid LPA results were obtained for 267 (98.5%) of the 271 new TB cases and 259 (98.1%) of the 264 previously treated TB cases. Valid culture-based DST results were available for 237 (87.5%) and 221 (83.7%) of new and previously treated cases respectively (Table 2). Overall, resistance data (either LPA and/or culture DST) was available for 269 new and 261 previously treated TB cases (Table 2). Contamination of subsequent subcultures was the most common reason for missing culture DST results. The line probe assay identified more rifampicin resistant cases than did culture-based DST, while more isoniazid resistance was identified through culture-based DST (Table 2). Overall, using both the LPA and culture-based DST results, 3.3% (9/269) and 7.7% (20/261) of new and previously treated cases were found to be infected with MDR-TB strains, with 5.2% (14/269) and 11.1% (29/261) infected with rifampicin resistant TB respectively (Table 2). Poly-resistance, most commonly isoniazid resistance combined with other first-line resistance apart from rifampicin was also frequently identified. Table 3 compares the resistance profile from culture-based DST with that from the LPA for the 29 cases defined as MDR-TB. Of the 26 MDR-TB cases identified using the LPA, 7 were not able to be assessed with conventional culture-based DST, while 2 cases were defined as MDR-TB based on rifampicin resistance from the LPA and isoniazid resistance from conventional culture-based DST. A further MDR-TB case was susceptible using the LPA. Second-line anti-tuberculosis resistance Among the 22 MDR-TB cases with culture-based DST available, 9 (41%) were found to have additional second-line resistance, including 7 (32%) with resistance to a fluoroquinolone or a second-line injectable agent or both (Table 3). Second-line resistance was also observed among strains with no first-line resistance and with mono- and poly-resistance to first-line drugs, most commonly resistance to ethionamide and capreomycin (Table 4). Estimating the burden of tuberculosis drug resistance in Khayelitsha In 2008, 5,791 cases of pulmonary tuberculosis were reported from primary care clinics in Khayelitsha. When the percentages of MDR-TB are applied to these case notification figures, 257 MDR- TB cases would have been diagnosed if all TB cases were tested: Table 1. HIV status, sex and age among new and previously treated culture positive TB cases (IQR = interquartile range). New TB Previously treated TB Total HIV negative HIV positive HIV status unknown Male Female Median age (IQR) Age Age Age 36+ doi: /journal.pone t (55% of known HIV status) 33 (12%) (43%) 32 (13) 58 (21%) 118 (44%) 95 (35%) (71% of known HIV status) 26 (10%) (36%) 36 (13) 34 (13%) 102 (39%) 128 (48%) PLoS ONE 3 November 2010 Volume 5 Issue 11 e13901 Table 2. Prevalence of drug resistance using line probe assay (LPA) results, conventional culture-based DST and combined among new and previously treated culture-positive TB cases. New TB cases Previously treated TB cases Total (positive culture) LPA results available Susceptible 244 (91%) 223 (86%) H-mono 11 (4.1%) 7 (2.7%) R-mono 4 (1.5%) 11 (4.2%) MDR-TB 8 (3.0%) 18 (6.9%) Any Rifampicin resistance 12 (4.5%) 29 (11.2%) Any Isoniazid resistance 19 (7.1%) 25 (9.7%) Culture-based DST available Susceptible to first-line 186 (79%) 167 (76%) First-line mono-resistance 35 (14.8%) 38 (17.2%) H-mono 8 (3.4%) 15 (6.8%) R-mono 2 (0.8%) 2 (0.9%) First-line poly-resistance 9 (3.8%) 5 (2.3%) MDR-TB Total 7 (3.0%) 11 (5.0%) MDR-TB with second line resistance 3 (1.3%) 5 (2.3%) XDR-TB 1 (0.4%) 1 (0.5%) Any Rifampicin resistance 9 (3.8%) 13 (5.9%) Any Isoniazid resistance 22 (9.3%) 31 (14.0%) Either LPA and culture DST MDR-TB 9 (3.3%) 20 (7.7%) Any Rifampicin resistance 14 (5.2%) 29 (11.1%) Any Isoniazid resistance 28 (10.4%) 41 (15.7%) doi: /journal.pone t002 Table 3. Resistance profile (first and second-line) for all MDR-TB cases (abbreviations: H = isoniazid, R = rifampicin, E = ethambutol, S = streptomycin, Z = pyrazinamide, Eto = ethionamide, Amk = amikacin, Km = kanamycin, Cm = capreomycin, Ofx = ofloxacin). Resistance profile culture-based DST LPA MDR-TB LPA Susc LPA R-mono no culture DST available 7 Susceptible 1 H 1 1 HR 2 HRE 1 1 HRS 1 HREZ 3 HRSZ 2 HREZ Eto 1 HRESZ Eto 1 HZ Amk 1 HRS Km 1 HRESZ Ofx 1 HRESZ Eto Km Amk Cm 1 HRESZ Eto Ofx 1 HRESZ Eto Ofx Km Amk Cm 2 Total doi: /journal.pone t003 PLoS ONE 4 November 2010 Volume 5 Issue 11 e13901 Table 4. Second-line resistance among strains not defined as MDR-TB. Resistance profile R Eto 1 H Eto 3 HS Eto 2 HZ Amk 1 Eto 7 Cm 6 Amk Cm Eto 1 Cm Ofx 1 doi: /journal.pone t004 Number 4.4% of the notified TB cases in that year (Figure 2). The majority (55%) would have been diagnosed among new, not previously treated TB suspects. These figures equate to an estimated notification rate of 51/100,000/year for MDR-TB, if all TB cases were to be tested. If MDR-TB among new cases represents direct transmission, then at least 141 (55%) of the estimated 257 MDR-TB cases are due to transmission. This proportion rises to 81% if we assume that a similar level of transmission occurs among the previously treated cases (Figure 2). Association between HIV infection, other factors and rifampicin resistant tuberculosis Given the significant burden of rifampicin resistance not defined as MDR-TB, associations with HIV infection and other factors were assessed with rifampicin resistance. Among HIV infected new cases, 5.3% (7/131) were rifampicin resistant, compared to 3.8% (4/105) among HIV negative new cases. For HIV infected previously treated cases, 13.9% (23/165) were rifampicin resistant compared to 5.7% (4/70) among HIV n
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