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Barbara Molina-Moya,1,2 Saddiq T Abdurrahman,3 Laura I Madukaji,4 Michel Kiréopori Gomgnimbou,5,6 Lizania Spinasse,5 Meissiner Gomes-Fernandes,1,2,7 Harrison Magdinier Gomes,5 Sarah Kacimi,5 Russell Dacombe,8 John S Bimba,4 Lovett Lawson,4 Christophe Sola,5 Luis E Cuevas,8,* Jose Dominguez1,2,* 1Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain; 2CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; 3National TB, Buruli Ulcer and Leprosy Control Programme, Abuja, Nigeria; 4Bingham University, Nasarawa State, Nigeria; 5Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette cedex, France; 6Centre Muraz, Bobo-Dioulasso, Burkina Faso; 7CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil; 8Liverpool School of Tropical Medicine, Liverpool, UK *These authors contributed equally to this work Objective: Nigeria ranks fourth among the high tuberculosis (TB) burden countries. This study describes the prevalence of drug resistance and the genetic diversity of Mycobacterium tuberculosis in Abuja’s Federal Capital Territory. Materials and methods: Two hundred and seventy-eight consecutive sputum samples were collected from adults with presumptive TB during 2013–2014. DNA was extracted from Löwenstein–Jensen cultures and analyzed for the identification of nontuberculous mycobacteria species, detection of drug resistance with line probe assays, and high-throughput spacer oligonucleotide typing (spoligotyping) using microbead-based hybridization. Results: Two hundred and two cultures were positive for M. tuberculosis complex, 24 negative, 38 contaminated, and 15 positive for nontuberculous mycobacteria. Five (2.5%) M. tuberculosis complex isolates were resistant to rifampicin (RIF) and isoniazid (multidrug resistant), nine (4.5%) to RIF alone, and 15 (7.4%) to isoniazid alone; two RIF-resistant isolates were also resistant to fluoroquinolones and ethambutol, and one multidrug resistant isolate was also resistant to ethambutol. Among the 180 isolates with spoligotyping results, 164 (91.1%) were classified as lineage 4 (Euro-American), 13 (7.2%) as lineage 5 (West African 1), two (1.1%) as lineage 2 (East Asia), and one (0.6%) as lineage 6 (West African 2). One hundred and fifty-six (86.7%) isolates were grouped in 17 clusters (2–108 isolates/cluster), of which 108 (60.0%) were grouped as L4.6.2/Cameroon (spoligotype international type 61). Conclusion: The description of drug resistance prevalence and genetic diversity of M. tuberculosis in this study may be useful for improving TB control in Nigeria. Keywords: tuberculosis, isoniazid, rifampicin, line probe assay, microbeads, spoligotyping

Methods: All State TB control programmes in Nigeria were requested to submit 25-50 smear-positive Ziehl-Neelsen (ZN) stained slides for screening during 2013-2014. DNA was extracted from 929 slides for spoligotyping and drug-resistance analysis using microbead-based flow-cytometry suspension arrays., Results: Spoligotyping results were obtained for 549 (59.1%) of 929 samples. Lineage 4 Cameroon sublineage (L4.6.2) represented half of the patterns, Mycobacterium africanum (L5 and L6) represented one fifth of the patterns, and all other lineages, including other L4 sublineages, represented one third of the patterns. Sublineage L4.6.2 was mostly identified in the north of the country whereas L5 was mostly observed in the south and L6 was scattered. The spatial distribution of genotypes had genetic geographic gradients. We did not obtain results enabling the detection of drug-resistance mutations., Conclusion/significance: We present the first national snapshot of the M. tuberculosis spoligotypes circulating in Nigeria based on ZN slides. Spoligotyping data can be obtained in a rapid and high-throughput manner with DNA extracted from ZN-stained slides, which may potentially improve our understanding of the genetic epidemiology of TB.

The lack of healthcare access contributes to large numbers of tuberculosis (TB) cases being missed and has led to renewed interest in outreach approaches to increase detection. It is however unclear whether outreach activities increase case detection or merely identify patients before they attend health facilities. We compared adults with cough of >2 weeks' duration recruited in health facilities (1202 participants) or in urban slums (2828 participants) in Nigeria. Participants provided demographic and clinical information and were screened using smear microscopy. The characteristics of smear-positive and smear-negative individuals were compared stratified by place of enrolment. Two hundred nine health facility participants (17.4%) and 485 community-based participants (16.9%) were smear positive for pulmonary TB. Community-based smear-positive cases were older (mean age, 36.3 vs. 31.8 years), had longer cough duration (10.3 vs. 6.8 weeks) and longer duration of weight loss (4.6 vs. 3.6 weeks) than facility-based cases; and they complained more of fever (87.4% vs. 74.6%), chest pain (89.0% vs. 67.0%) and anorexia (79.5% vs. 55.5%). Community smear-negative participants were older (mean, 39.4 vs. 34.0 years), were more likely to have symptoms and were more likely to have symptoms of longer duration than smear-negative facility-based participants. Patients with pulmonary TB identified in the community had more symptoms and longer duration of illness than facility-based patients, which appeared to be due to factors differentially affecting access to healthcare. Community-based activities targeted at urban slum populations may identify a different TB case population than that accessing stationary services.

Background: A major impediment to the treatment of TB is a diagnostic process that requires multiple visits. Descriptions of patient costs associated with diagnosis use different protocols and are not comparable., Methods: We aimed to describe the direct costs incurred by adults attending TB diagnostic centres in four countries and factors associated with expenditure for diagnosis. Surveys of 2225 adults attending smear-microscopy centres in Nigeria, Nepal, Ethiopia and Yemen. Adults >18 years with cough >2 weeks were enrolled prospectively. Direct costs were quantified using structured questionnaires. Patients with costs >75(th) quartile were considered to have high expenditure (cases) and compared with patients with costs <75(th) quartile to identify factors associated with high expenditure., Results: The most significant expenses were due to clinic fees and transport. Most participants attended the centres with companions. High expenditure was associated with attending with company, residing in rural areas/other towns and illiteracy., Conclusions: The costs incurred by patients are substantial and share common patterns across countries. Removing user fees, transparent charging policies and reimbursing clinic expenses would reduce the poverty-inducing effects of direct diagnostic costs. In locations with limited resources, support could be prioritised for those most at risk of high expenditure; those who are illiterate, attend the service with company and rural residents.

Objective: Underdetection of TB is a major problem in sub-Saharan Africa. WHO recommends countries should have at least 1 laboratory per 100,000 population. However, this recommendation is not evidence based., Methods: We analysed surveillance data of the Nigerian National TB Control Programme (2008-2012) to describe TB case detection rates, their geographical distribution and their association with the density of diagnostic laboratories and HIV prevalence., Results: The median CDR was 17.7 (range 4.7-75.8%) in 2008, increasing to 28.6% (range 10.6-72.4%) in 2012 (P < 0.01). The CDR2012 was associated with the 2008 baseline; however, states with CDR2008 < 30% had larger increases than states with CDR2008 > 30. There were 990 laboratories in 2008 and 1453 in 2012 (46.7% increase, range by state -3% to +118). The state CDR2012 could be predicted by the laboratory density (P < 0.001), but was not associated with HIV prevalence or the proportion of smear-positive cases. CDR2012 and laboratory density were correlated among states having < and > than 1 laboratory per 100,000 population., Conclusion: There are large variations in laboratory density and CDR across the Nigerian states. The CDR is associated with the laboratory density. A much larger number of diagnostic centres are needed. It is likely that a laboratory density above the recommended WHO guideline would result in even higher case detection, and this ratio should be considered a minimum threshold., (© 2015 John Wiley & Sons Ltd.)

Tuberculosis (TB) is a global public health problem, with the highest burden occurring in low-income countries. In these countries, the use of more sensitive diagnostics, such as Xpert MTB/RIF (Xpert), is still limited by costs. A cost-saving strategy to diagnose other diseases is to pool samples from various individuals and test them with single tests. The samples in positive pool samples are then retested individually to identify the patients with the disease. We assessed a pooled testing strategy to optimize the affordability of Xpert for the diagnosis of TB. Adults with presumptive TB attending hospitals or identified by canvassing of households in Abuja, Nigeria, were asked to provide sputum for individual and pooled (4 per pool) testing. The agreement of the results of testing of individual and pooled samples and costs were assessed. A total of 738 individuals submitted samples, with 115 (16%) being Mycobacterium tuberculosis positive. Valid Xpert results for individual and pooled samples were available for 718 specimens. Of these, testing of pooled samples detected 109 (96%) of 114 individual M. tuberculosis-positive samples, with the overall agreement being 99%. Xpert semiquantitative M. tuberculosis levels had a positive correlation with the smear grades, and the individual sample-positive/pooled sample-negative results were likely due to the M. tuberculosis concentration being below the detection limit. The strategy reduced cartridge costs by 31%. Savings were higher with samples from individuals recruited in the community, where the proportion of positive specimens was low. The results of testing of pooled samples had a high level of agreement with the results of testing of individual samples, and use of the pooled testing strategy reduced costs and has the potential to increase the affordability of Xpert in countries with limited resources., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Many patients treated for tuberculosis (TB) in low and middle income countries are treated based on clinical suspicion without bacteriological confirmation. This is often due to lack of rapid simple accurate diagnostics and low healthcare provider confidence in the predictive value of current tests. We previously reported in an animal TB model that levels of host markers rapidly change in response to treatment initiation., Methods: We assessed the potential of host biomarker kinetics of TB patients during the first two weeks of therapy to identify patients responding to treatment. Adult patients clinically diagnosed with and treated for TB, 29 in Nigeria and 24 in Nepal, were analyzed., Results: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB. A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear-negative culture positive patients and correctly excluded TB in all nine culture negative patients., Conclusions: Monitoring of early IP-10 responses to treatment could form the basis of a simplified assay and could help identify patients who were erroneously clinically diagnosed with TB or those infected with drug resistant strains on inappropriate treatment. We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation.

Introduction: Since the endorsement of GeneXpert MTB/RIF by the WHO, many countries have embarked on implementing this technology., Objective: We outline the cost of installing GeneXpert in district hospitals in Abuja, Nigeria., Methods: We prospectively documented costs related to the installation of GeneXpert at five sites. Costs were collected from receipts received from suppliers and normalized to USD 2012 values., Results: Costs were often identified after initiating installation for many reasons. Installation varied widely between sites with sufficient space and power supply; sites with insufficient space or power supply and costs not directly associated with site installation. The basic cost for installation was USD 2,621.98 per machine. Sites that required additional space cost close to USD 7,000.00., Conclusion: Space and power requirements have a significant effect on installation costs. Countries need to carefully consider the placement of Xpert machines based on the quality and size of the available infrastructure.

Background: Nigeria is faced with a high burden of Human Immunodeficiency Virus (HIV) infection and multidrug-resistant tuberculosis (MDR-TB). Treatment outcomes among MDR-TB patients registered across the globe have been poor, partly due to high loss-to-follow-up. To address this challenge, MDR-TB patients in Nigeria are hospitalized during the intensive-phase(IP) of treatment (first 6-8 months) and are provided with a package of care including standardized MDR-TB treatment regimen, antiretroviral therapy (ART) and cotrimoxazole prophylaxis (CPT) for HIV-infected patients, nutritional and psychosocial support. In this study, we report the end-IP treatment outcomes among them., Methods: In this retrospective cohort study, we reviewed the patient records of all bacteriologically-confirmed MDR-TB patients admitted for treatment between July 2010 and October 2012., Results: Of 162 patients, 105(65%) were male, median age was 34 years and 28(17%) were HIV-infected; all 28 received ART and CPT. Overall, 138(85%) were alive and culture negative at the end of IP, 24(15%) died and there was no loss-to-follow-up. Mortality was related to low CD4-counts at baseline among HIV-positive patients. The median increase in body mass index among those documented to be underweight was 2.6 kg/m2 (p<0.01) and CD4-counts improved by a median of 52 cells/microL among the HIV-infected patients (p<0.01)., Conclusions: End-IP treatment outcomes were exceptional compared to previously published data from international cohorts, thus confirming the usefulness of a hospitalized model of care. However, less than five percent of all estimated 3600 MDR-TB patients in Nigeria were initiated on treatment during the study period. Given the expected scale-up of MDR-TB care, the hospitalized model is challenging to sustain and the national TB programme is contemplating to move to ambulatory care. Hence, we recommend using both ambulatory and hospitalized approaches, with the latter being reserved for selected high-risk groups.

Background: This study compares Mycobacterium tuberculosis culture isolation and drug sensitivity testing (DST) using solid (LJ) and liquid (BACTEC-MGIT-960) media in Nigeria., Methods: This was a cross sectional survey of adults attending reference centres in Abuja, Ibadan and Nnewi with a new diagnosis of pulmonary tuberculosis (TB) or having failed the first-line TB treatment. Patients were requested to provide three sputum specimens for smear-microscopy and culture on LJ and BACTEC-MGIT-960. Positive cultures underwent DST for streptomycin, isoniazid, rifampicin and ethambutol., Results: 527 specimens were cultured. 428 (81%) were positive with BACTEC-MGIT-960, 59 (11%) negative, 36 (7%) contaminated and 4 (1%) had non-tuberculosis mycobacteria (NTM). 411 (78%) LJ cultures were positive, 89 (17%) negative, 22 (4%) contaminated and 5 (1%) had NTM. The mean (SD) detection time was 11 (6) and 30 (11) days for BACTEC-MGIT-960 and LJ. DST patterns were compared in the 389 concordant positive BACTEC-MGIT-960 and LJ cultures. Rifampicin and isoniazid DST patterns were similar. Streptomycin resistance was detected more frequently with LJ than BACTEC-MGIT-960 and ethambutol resistance was detected more frequently with BACTEC-MGIT-960 than LJ, but differences were not statistically significant. MDR-TB was detected in 27 cases by LJ and 25 by BACTEC-MGIT-960 and using both methods detected 29 cases., Conclusions: There was a substantial degree of agreement between the two methods. However using the two in tandem increased the number of culture-positive patients and those with MDR-TB. The choice of culture method should depend on local availability, cost and test performance characteristics.

Background: Nigeria has the tenth highest burden of tuberculosis (TB) among the 22 TB high-burden countries in the world. This study describes the biodiversity and epidemiology of drug-susceptible and drug-resistant TB in Ibadan, Nnewi and Abuja, using 409 DNAs extracted from culture positive TB isolates., Methodology/principal Findings: DNAs extracted from clinical isolates of Mycobacterium tuberculosis complex were studied by spoligotyping and 24 VNTR typing. The Cameroon clade (CAM) was predominant followed by the M. africanum (West African 1) and T (mainly T2) clades. By using a smooth definition of clusters, 32 likely epi-linked clusters related to the Cameroon genotype family and 15 likely epi-linked clusters related to other "modern" genotypes were detected. Eight clusters concerned M. africanum West African 1. The recent transmission rate of TB was 38%. This large study shows that the recent transmission of TB in Nigeria is high, without major regional differences, with MDR-TB clusters. Improvement in the TB control programme is imperative to address the TB control problem in Nigeria.

Objectives: To determine the levels of resistance to first-line tuberculosis drugs in three cities in three geopolitical zones in Nigeria., Methods: A total of 527 smear-positive sputum samples from Abuja, Ibadan and Nnewi were cultured on BACTEC- MGIT 960. Drug susceptibility tests (DST) for streptomycin, isoniazid, rifampicin and ethambutol were performed on 428 culture-positive samples on BACTEC-MGIT960., Results: Eight per cent of the specimens cultured were multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) with varying levels of resistance to individual and multiple first-line drugs. MDR was strongly associated with previous treatment: 5% of new and 19% of previously treated patients had MDR-TB (OR 4.1 (95% CI 1.9-8.8), P = 0.001) and with young adult age: 63% of patients with and 38% without MDR-TB were 25-34 years old (P = 0.01). HIV status was documented in 71%. There was no association between MDR-TB and HIV coinfection (P = 0.9) and gender (P > 0.2 for both)., Conclusions: MDR-TB is an emerging problem in Nigeria. Developing good quality drug susceptibility test facilities, routine monitoring of drug susceptibility and improved health systems for the delivery of and adherence to first- and second-line treatment are imperative to solve this problem., (© 2011 Blackwell Publishing Ltd.)

The identification of early markers that predict the response to anti-tuberculosis treatment would facilitate evaluation of new drugs and improve patient management. This study aimed to determine whether selected acute phase proteins and micronutrients measured at the time of diagnosis and during the first weeks of treatment could predict treatment responses during the 2-month standard intensive phase of therapy. For this purpose, alpha1-antitrypsin, alpha1-acid glycoprotein, alpha2-macroglobulin, C-reactive protein, C3, C4, zinc, copper and selenium concentrations were measured in Brazilian patients with smear-positive tuberculosis at the time of diagnosis and 1, 3, 5 and 8 weeks after initiation of therapy. Patients were classified into fast (n=29), intermediate (n=18) and slow responders (n=10) if they were smear-negative at 3, 5 or 8 weeks of treatment. alpha1-acid glycoprotein on enrolment and 1 week of treatment, alpha1-antitrypsin at week 1 and C-reactive protein and C3 after 3 weeks of therapy were higher in slow responders than in fast responders. alpha1-antitrypsin and alpha1-acid glycoprotein may be helpful in predicting treatment response at the time of initiation of therapy, and could be used as early markers to identify patients with an increased likelihood of treatment failure.