Epidemic Levels of Drug Resistant Tuberculosis (MDR and XDR-TB) in a High HIV Prevalence Setting in Khayelitsha, South Africa

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

Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial

Background: Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden. Methods and Findings: A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33–0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32–1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06–1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63–0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53–0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic. Conclusions: These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants

Characterization and gene expression of transmissible Mycobacterium Tuberculosis strains in South Africa

Thesis (MSc) -- Stellenbosch University, 2008ENGLISH ABSTRACT: The Mycobacterium tuberculosis Beijing strain family is a dominant strain family in most countries world wide, including South Africa. It has been suggested that this strain family has unique properties. These include the ability to evade the protective effect of Bacillus Calmette-Guérin vaccination, spread more readily and the more frequent acquisition of drug resistance. These properties might be the reasons for the Beijing strain’s successful transmission. Comparative genomics have suggested that strains from the Beijing family can be broadly grouped into typical and atypical strains according to the presence or absence of an IS6110 insertion in the NTF region in the genome of Mycobacterium tuberculosis. Phylogenetic analysis showed that these two groups originated from a common progenitor. However, the atypical Beijing strain has only rarely been identified. The atypical Beijing strains are also not frequently associated with drug resistance, is attenuated and therefore do not spread readily. In contrast, by applying molecular epidemiological techniques, this study showed that an atypical Beijing strain acquired drug resistance and was spreading amongst tuberculosis re-treatment patients in the Eastern Cape province of South Africa. Further molecular analysis showed that this strain had a high fitness cost mutation in the rpoB gene, conferring rifampicin resistance. This correlates with in vitro generated rpoB mutants. The human immune deficiency virus/tuberculosis co-infection was found to be a significant co-factor, which allowed the atypical Beijing strain to be transmitted. Therefore, the attenuated atypical Beijing strain can overcome its fitness cost in high human immune deficiency virus burdened communities and may cause ongoing transmission. This raises concern for the spread of all drug-resistant strains in vulnerable populations. By analysing a longitudinal reference database at the University of Stellenbosch, it has been observed that the strain dynamics within a strain family differs. There are large and small clusters in the Beijing strain family which is suggestive of more and less transmissible strains. Comparative proteomic analysis by 2-D gel electrophoresis identified 64 protein spots which were different between a large and small cluster in the Beijing strain family. Similarly, 59 protein spots were found different between the attenuated atypical Beijing strain and the typical large Beijing cluster. By comparing the atypical Beijing strain to the small Beijing cluster it was found that 132 protein spots were different between the two strains. These results strongly suggest that differential expression of certain genes is associated with differential transmission of different Beijing sub-lineages. The same may be true for other Mycobacterium tuberculosis strain families. It is likely that the bacterial genomic background play a more dominant role in the differential transmission of certain Mycobacterium tuberculosis strains, than host or programmatic related factors. A more comprehensive study, which involves the bacterium, host, and the tuberculosis control program, is needed to prove this assumption.AFRIKAANSE OPSOMMING: Die Mycobacterium tuberculosis Beijing familie is ‘n prominent in meeste lande wêreld wyd, insluitende Suid-Afrika. Bevindings toon dat hierdie familie unieke eienskappe besit. Dit sluit in die vermoëe om die uitwerking van die Bacillus Calmette-Guérin vaksien te ontduik, maklik te versprei, en die vermoeë om meer gereeld middel weerstandigheid te verkry, en daarom so suksesvol is. Vergelykbare genomika het getoon dat stamme wat aan die Beijing familie behoort, in twee sub-groepe verdeel kan word naamlik, tipies en atipies as gevolg van die aanwesigheid of afwesigheid van ‘n spesifieke IS6110 invoeging in die NTF area van die Mycobacterium tuberculosis genoom. Filogenetiese analises het verder getoon dat die twee groepe ‘n gemeenskaplike oorsprong het maar die atipiese Beijing sub-groep is meer skaars en word nie dikwels met middel weerstandigheid geassosieer nie, en versprei daarom nie so maklik nie. In teenstelling, deur die toepassing van molekulere epidemiologiese tegnieke, het hierdie studie getoon dat daar ‘n atipiese Beijing stam in die Oos-Kaap provinsie van Suid-Afrika gevind is, wat wel middel weerstandig is en versprei het tussen tuberkulose pasiente wat weer op behandeling is. Verdere molekulere analises het getoon dat die atipiese Beijing stam ‘n hoë fiksheid verlies mutasie in die rpoB geen het wat rifampisien weerstandigheid veroorsaak. Hierdie bevinding korreleer met in vitro gegenereerde rpoB mutante. Die studie het gevind dat menslike immuniteitsgebrek-virus/tuberkulose ko-infeksie ‘n belangrike faktor was in die verspreiding van hierdie stam. Dus, die minder virulente atipiese Beijing stam kan fiksheid verlies oorkom in gemeenskappe wat belas is met menslike imuniteits virus, en kan dus voortdurende transmisie veroorsaak. Hierdie bevinding wek kommer oor die verspreiding van alle middel weerstandige Mycobacterium tuberculosis stamme in kwesbare gemeenskappe. Mycobacterium tuberculosis Die ontleding van ‘n aaneenlopende databasis van die Universiteit van Stellenbosch het getoon dat die dinamika van stamme binne ‘n stam familie verskil. Daar kom groot en klein groepe in die Beijing stam familie voor wat bes moontlik op stamme wat met onderskeidelik ‘n hoe en lae oordraaglikheid dui. Vergelykende proteomiese analise deur middle van 2-D elektroforese het 64 protein verskille opgelewer tussen ‘n groot en klein stam van die Beijing stam familie. Netso is 59 protein verskille gevind toe die groot tipiese Beijing stam en die geattenueerde atipiese Beijing stam vergelyk word. “n Vergelyking tussen die klein tipiese Beijing stam en die atipiese Beijing stam het 132 protein verskille getoon. Hierdie resultate laat ‘n sterk vermoede dat differensiele uitdrukking van sekere gene geassosieer kan word met differensiele oordraag van verskillende Beijing stamme. Dieselfde mag ook geld vir ander Mycobacterium tuberculosis stam families. Dit is moontlik dat die genomiese agtergrond van die bakterium ‘n meer dominante rol by die differensiele oordraag van sekere Mycobacterium tuberculosis stamme het as ander faktore rakende die draer van die tuberkulose infeksie, of die tuberkulose-beheerprogram. Om hierdie aanname te staaf sal ‘n meer omvattende studie wat die Mycobacterium tuberculosis bakterium, die draer, en die Mycobacterium tuberculosis tuberkulose beheerprogram betrek, nodig wees

Belangrike ontwikkelings in gesondheidsdienslewering in die republiek van suid-afrika gedurende die sewentigerjare

A number of major developments have brought about important changes in the delivery and co-ordination of health services in South Africa. Some of these developments are: — the hospital-centric community-directed health services which were developed in the national states; — the changes to programme-budgeting which highlighted priority areas; — the Health Act 63 o f 1977 which provides for a formal structure for co-ordination of health services and the development of national health policy; — rationalisation in the civil service by which one Department of Health, Welfare and Pensions was created; — the Health Services Facilities Plan announced by the Minister of Health in 1980. This plan will greatly enhance the development of comprehensive health services for the South African community. The plan describes six levels according to which health services will be developed: providing for basic health needs; health education; primary health care (including self-care, community responsibility, community nursing and community health centres); the community hospital; the regional hospital; the academic hospital

Univariate and multivariate analyses to assess associations with rifampicin resistance among all, previously treated, and HIV positive culture positive TB cases.

<p>Univariate and multivariate analyses to assess associations with rifampicin resistance among all, previously treated, and HIV positive culture positive TB cases.</p

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 = of

<p>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).</p

Estimating the burden of rifampicin resistant tuberculosis in Khayelitsha.

<p>Estimating the burden of rifampicin resistant tuberculosis in Khayelitsha.</p

Second-line resistance among strains not defined as MDR-TB.

<p>Second-line resistance among strains not defined as MDR-TB.</p

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.

<p>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.</p

Proportion of HIV-infected and -uninfected participants initiating TB treatment by time to treatment initiation for both study arms, ITT analysis.

<p>Xpert: solid line; routine: dashed line. (A) HIV-infected individuals (<i>p</i><0.001); (B) HIV-uninfected individuals (<i>p</i> = 0.778).</p