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Abstract The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for 100 years and prevents disseminated tuberculosis and death in young children. However, it shows only partial efficacy against pulmonary tuberculosis (TB) in adults, so new vaccines are urgently needed. The protective efficacy of BCG depends on T cells, which are typically activated by pathogen-derived protein antigens that bind to highly polymorphic major histocompatibility complex (MHC) molecules. Some T cells recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. Whether live whole cell vaccines, like BCG, can induce durable expansions of DURT cells in humans is not known. We used combinatorial tetramer staining, multi-parameter flow cytometry, and immunosequencing to comprehensively characterize the effect of BCG on activation and expansion of DURT cell subsets. We examined peripheral blood mononuclear cells (PBMC) derived from a Phase I study of South African adults in which samples were archived at baseline, 3 weeks, and 52 weeks post-BCG revaccination. We did not observe a change in the frequency of total mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells at 52 weeks post-BCG. However, immunosequencing revealed a set of TCR-δ clonotypes that were expanded at 52 weeks post-BCG revaccination. These expanded clones expressed the Vδ2 gene segment and could be further defined on the basis of biochemical similarity into several ‘meta-clonotypes’ that likely recognize similar epitopes. Our data reveal that BCG vaccination leads to durable expansion of DURT cell clonotypes despite a limited effect on total circulating frequencies in the blood and have implications for defining the immunogenicity of candidate whole cell TB vaccines.

Summary: Background: Non-protein antigen classes can be presented to T cells by near-monomorphic antigen-presenting molecules such as CD1, MR1, and butyrophilin 3A1. Such T cells, referred to as donor unrestricted T (DURT) cells, typically express stereotypic T cell receptors. The near-unrestricted nature of DURT cell antigen recognition is of particular interest for vaccine development, and we sought to define the roles of DURT cells, including MR1-restricted MAIT cells, CD1b-restricted glucose monomycolate (GMM)-specific T cells, CD1d-restricted NKT cells, and γδ T cells, in vaccination against Mycobacterium tuberculosis. Methods: We compared and characterized DURT cells following primary bacille Calmette-Guerin (BCG) vaccination in a cohort of vaccinated and unvaccinated infants, as well as before and after BCG-revaccination in adults. Findings: BCG (re)vaccination did not modulate peripheral blood frequencies, T cell activation or memory profiles of MAIT cells, CD1b-restricted GMM-specific and germline-encoded mycolyl-reactive (GEM) cells or CD1d-restricted NKT cells. By contrast, primary BCG vaccination was associated with increased frequencies of γδ T cells as well as a novel subset of CD26+CD161+TRAV1-2− IFN-γ-expressing CD4+ T cells in infants. Interpretation: Our findings, that most DURT cell populations were not modulated by BCG, do not preclude a role of BCG in modulating other qualitative aspects of DURT cells. More studies are required to understand the full potential of DURT cells in new TB vaccine strategies. Funding: Aeras, the National Institutes of Health, and the Bill and Melinda Gates Foundation.

Category: Basic Sciences/Biologics, Midfoot/Forefoot Introduction/Purpose: First tarsometatarsal (TMT) joint fusion is indicated for several underlying causes of first ray dysfunction and pain, including arthritis, traumatic injury, and recurrent hallux valgus. Preparation of the joint surface by denuding the articular cartilage is a key step for arthrodesis, as inadequate preparation may result in poor fixation and non-union. However, excessive removal of cartilage and bone may result in excessive shortening of the ray. Despite the importance of joint preparation on the outcomes of fusion, the effects of using a bone saw versus osteotome on ray length is poorly documented in the literature. The purpose of this study was to investigate whether utilization of an osteotome or saw would minimize shortening of the first ray in TMT arthrodesis. Methods: Ten fresh-frozen cadaver specimens without evidence of musculoskeletal abnormalities were used for this anatomic dissection study. A medial incision was made along the first ray from the medial aspect of the medial cuneiform to the base of the first metatarsal. The first TMT joint was exposed through transverse capsulotomy. The soft tissues surrounding the joint were not removed from the bone. The specimens were randomly assigned to undergo cartilage removal and joint preparation using either an osteotome (n=5) or saw (n=5). Care was taken to reach the plantar-most aspect of the joint. Fusion was then performed using a cross-screw construct through the dorsal aspect of the proximal phalanx and the medial cuneiform. Pre- and post-operative x- rays were taken with a radiopaque ruler in the field, and length changes were compared between osteotome and sawblade groups. Results: The average change in metatarsal length was significantly smaller in the osteotome group (1.6 mm) as compared to the saw group (4.4 mm) (p=0.031). The average percent change in metatarsal length was also significantly smaller in the osteotome group (3.0%) compared to the saw group (8.4%) (p=0.025). There was no significant difference between the two groups with respect to change in cuneiform length. The osteotome group demonstrated a significantly smaller average measured change (3.0 mm vs. 6.9 mm, p=0.001) and percent change (4.1% vs. 9.3%, p

Cellular identity between generations of developing cells is propagated through the epigenome particularly via the accessible parts of the chromatin. It is now possible to measure chromatin accessibility at single-cell resolution using single-cell assay for transposase accessible chromatin (scATAC-seq), which can reveal the regulatory variation behind the phenotypic variation. However, single-cell chromatin accessibility data are sparse, binary, and high dimensional, leading to unique computational challenges. To overcome these difficulties, we developed PRISM, a computational workflow that quantifies cell-to-cell chromatin accessibility variation while controlling for technical biases. PRISM is a novel multidimensional scaling-based method using angular cosine distance metrics coupled with distance from the spatial centroid. PRISM takes differences in accessibility at each genomic region between single cells into account. Using data generated in our lab and publicly available, we showed that PRISM outperforms an existing algorithm, which relies on the aggregate of signal across a set of genomic regions. PRISM showed robustness to noise in cells with low coverage for measuring chromatin accessibility. Our approach revealed the previously undetected accessibility variation where accessible sites differ between cells but the total number of accessible sites is constant. We also showed that PRISM, but not an existing algorithm, can find suppressed heterogeneity of accessibility at CTCF binding sites. Our updated approach uncovers new biological results with profound implications on the cellular heterogeneity of chromatin architecture.

A comparative study to evaluate contamination in cultures of morning sputum samples, comparing those collected at home under currently recommended conditions and those collected under supervision after patient orientation and education. The home and supervised collection groups produced 43 and 76 sputum samples, respectively. The contamination rate was nearly 3-times higher among samples collected at home than among those collected under supervision (37% vs. 13%, p < 0.05; OR = 0.25). The simple educational and hygiene measures described can decrease the contamination rate among sputum samples collected for diagnostic culture.Realizou-se um estudo comparativo para avaliar a contaminação em culturas de amostras matinais de escarro coletadas em domicílio sob condições recomendadas atualmente e amostras coletadas sob supervisão após orientação e educação dos pacientes. Os grupos de coleta domiciliar e supervisionada produziram 43 e 76 amostras, respectivamente. A taxa de contaminação foi aproximadamente 3 vezes maior nas amostras coletadas em domicílio do que naquelas coletadas sob supervisão (37% vs.13%; p < 0,05; OR = 0,25). As simples medidas educacionais e de higiene descritas podem reduzir a taxa de contaminação de amostras de escarro coletadas para culturas diagnósticas.

Abstract The role of TGF-β TNF-α FasL and Bcl-2 in apoptosis of CD4 T-cells during active TB was studied. Coculture of PBMC from TB patients with neutralizing antibodies to TGF-β or TNF-α decreased spontaneous (P ≰ 0.05) and MTB-induced (P≰ 0.02) T-cell apoptosis by 50–90%, but effects were not additive. Interestingly, only levels of TGF-β in supernatants correlated with rates of spontaneous and MTB-induced apoptosis. FasL surface and mRNA expression were higher in unstimulated and MTB-stimulated PBMC from patients than controls, and neutralization of FasL abrogated apoptosis of T-cells from patients only. Intracellular Bcl-2 protein was lower among unstimulated CD4 T-cells from patients than those from controls (P ≰ 0.02), and MTB stimulation reduced intracellular Bcl-2 content in CD4 T-cells from patients only (P ≰ 0.001). These findings may indicate that, during TB, predisposition of CD4 T-cells to apoptosis may involve both low expression of Bcl-2, and excessive expression of TGF-β TNF-α and FasL. [ABSTRACT FROM AUTHOR]

Wheatstone invented the first stereoscopic display on record in 1834. Numerous approaches to the display of stereo imagery have been demonstrated since; however, all suffer from various drawbacks. Stereoscopic displays typically require the user to wear special headgear. Autostereoscopic displays typically have tight limitations on the position of the viewer’s head. We investigate an architecture consisting of two readily available, inexpensive twisted nematic liquid crystal display (TN-LCD) panels sandwiched together to form a compact, rugged stereoscopic display. We describe the theory of operation, the experimental determination of the liquid crystal display modulation characteristics, and modifications to the theory of operation, as a consequence of the experimental results. [ABSTRACT FROM AUTHOR]

This study sought to assess perceptions towards and reasons for participation in research bronchoscopy studies in a high TB burden urban setting. Additionally, the study aimed to identify areas of pre- and post-procedural concern among healthy adults approached to participate in research bronchoscopy. A cross sectional qualitative study was undertaken at the Uganda-Case Western Reserve University Collaboration Tuberculosis Research Project Clinic at Mulago National Referral Hospital in Kampala, Uganda. In-depth interviews were conducted with participants at their pre-bronchoscopy visit (n = 17) and after they had undergone bronchoscopy (n = 23) to examine their perceptions and experiences with the procedure. Following consent, all interviews were audio recorded and later transcribed and typed in MS WORD. Local language interviews were translated into English by the social science interviewers. Qualitative analysis was performed manually following an inductive and emergent approach typical in thematic analysis. This study was approved by the Makerere University School of Social Sciences Research Ethics Committee (MAKSS REC 09.18.220) and registered with the Uganda National Council for Science and Technology (UNCST SS4785). Overall willingness to participate in bronchoscopy was high as many participants viewed the study as primarily a means of getting free health checks and determining their health status. Notably, despite extensive face to face counseling for this study coupled with the fact that our participants had been involved in prior research at the site, therapeutic misconception still played a pivotal role in willingness to participate in research bronchoscopy. Therapeutic misconception has important ethical and research implications in clinical research, which requires strategies to tackle it, even among a pool of potential participants who are knowledgeable about a disease or clinical care procedures. Continuous awareness and knowledge building about the difference between being a trial participant and therapeutic misconception must become a mainstay in trials to improve the process of informed consent for future research bronchoscopy studies.

BackgroundThe search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.MethodsBronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry.ResultsThe bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants.ConclusionThis observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.Clincialtrials.gov, NCT01119521.

OBJECTIVE: To compare tuberculosis cure rates among patients supervised by household members or health care workers. METHODS: Prospective cohort study of 171 patients treated by the program in Vitoria, Southeastern Brazil, from 2004 to 2007. Each patient was followed-up for six months until the end of the treatment. Of the patients studied, a household member supervised 59 patients and healthcare workers supervised 112 patients. Patients' sociodemographic and clinic data were analyzed. Differences between groups were assessed using chi-square test or Student's t-test. Significance level was set at 5%. RESULTS: Most patients had smear positive, culture confirmed pulmonary tuberculosis. Two patients were HIV-positive. There were more illiterate patients in the healthcare-supervised group, in comparison to those supervised by their families (p=0.01). All patients supervised by a household member were cured compared to 90% of the patients supervised by health care workers (p = 0.024). CONCLUSIONS: Successful tuberculosis treatment was more frequent when supervised by household members.OBJETIVO: Comparar los resultados de cura por tuberculosis entre pacientes supervisados por ele miembro familiar y por el profesional de salud. MÉTODOS: Estudio de cohorte prospectivo de 171 pacientes de Vitória, sureste de Brasil, en el período de 2004 a 2007. Cada paciente fue acompañado por seis meses hasta la finalización del tratamiento. De los pacientes estudiados, 59 pacientes tratados eran supervisados por un miembro familiar y 112 por los profesionales de salud. Fueron evaluados datos sociodemográficos y clínicos de los pacientes. Diferencias entre los grupos de estudio fueron evaluadas utilizando la prueba Chi-cuadrado o prueba t de Student al nivel de significancia de 5%. RESULTADOS: La mayoría de los sujetos de estudio presentaron bacioscopia positiva y cultivo confirmado para tuberculosis. Dos pacientes tenían serología positiva para HIV. Un número mayor de pacientes en el grupo supervisado por profesionales de salud no eran alfabetizados, comparado con aquellos pacientes del grupo supervisado por miembros familiares (p=0,01). Todos los pacientes supervisados por un familiar fueron curados, frente a 90% de los pacientes supervisados por los profesionales de salud (p=0,024). CONCLUSIONES: El éxito del tratamiento de tuberculosis fue mayor cuando se supervisó por un familiar.OBJETIVO: Comparar os resultados de cura por tuberculose entre pacientes supervisionados pelo membro familiar e pelo profissional de saúde. MÉTODOS: Estudo de coorte prospectiva de 171 pacientes de Vitória, ES, no período de 2004 a 2007. Cada paciente foi acompanhado por seis meses até a finalização do tratamento. Dos pacientes estudados, 59 pacientes tratados eram supervisionados por um membro familiar e 112 pelos profissionais de saúde. Foram avaliados dados sociodemográficos e clínicos dos pacientes. Diferenças entre os grupos de estudo foram avaliadas utilizando o teste qui-quadrado ou teste t de Student ao nivel de significância de 5%. RESULTADOS: A maioria dos sujeitos do estudo apresentaram bacioscopia positiva e cultura confirmada para tuberculose. Dois pacientes tinham sorologia positiva para HIV. Um número maior de pacientes no grupo supervisionado por profissionais de saúde não eram alfabetizados, comparado com aqueles pacientes do grupo supervisionado por membros familiares (p = 0,01). Todos os pacientes supervisionados por um familiar foram curados, frente a 90% dos pacientes supervisionados pelos profissionais de saúde (p=0,024). CONCLUSÕES: O sucesso do tratamento de tuberculose foi maior quando supervisionado por um familiar.

In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.

RATIONALE:Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. OBJECTIVES:We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment. MATERIALS AND METHODS:We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24. RESULTS:There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p

BACKGROUND:Factors related to the development of extrapulmonary forms of tuberculosis (EPTB) are still poorly understood, particularly in high-endemic countries like Brazil. The objective of the paper is to determine host and Mycobacterium tuberculosis (MTB) strain-related factors associated with the development of EPTB in Espírito Santo state, Brazil. METHODS AND FINDINGS:We conducted a retrospective laboratory-based surveillance study of new tuberculosis (TB) cases diagnosed in Espírito Santo state, Brazil between 1998 and 2007. We genotyped 612 isolates of MTB from 606 TB patients using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing and compared sociodemographic and clinical characteristics of patients with pulmonary TB (PTB) and EPTB. Among 606 patients, 464 (77%) had PTB, 79 (13%) had EPTB, 51 (8%) had both, and 12 (2%) had miliary TB. The IS6110 RFLP analysis demonstrated that 250 (41%) isolates belonged to clustered RFLP patterns, 27 (11%) of which were from EPTB. We identified 73 clusters including 35 (48%) composed of 2 isolates each. By spoligotyping, 506 (83%) MTB isolates fell into known patterns and 106 (17%) fell into patterns with no family assignment; 297 (48%) isolates belonged to the Latin-American Mediterranean family. Higher school level (4-7 years OR: 0.16 95% CI 0.34-0.73 and > 8 years of education, OR 0.06 95% CI 0.009-0.50) white ethnicity (OR: 2.54 95% CI 1.03-6.25) and HIV infection (OR: 16.83 95% CI 5.23-54.18) were associated with EPTB. No specific strain lineage or percentage of clustering was associated with EPTB. CONCLUSIONS:These results demonstrate that risk factors for EPTB are related more to host than to MTB strain lineage characteristics.

Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites.African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found.Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved.ClinicalTrials.gov NCT00144417.

Recent studies suggest that M. tuberculosis lineage and host genetics interact to impact how active tuberculosis presents clinically. We determined the phylogenetic lineages of M. tuberculosis isolates from participants enrolled in the Tuberculosis Trials Consortium Study 28, conducted in Brazil, Canada, South Africa, Spain, Uganda and the United States, and secondarily explored the relationship between lineage, clinical presentation and response to treatment. Large sequence polymorphisms and single nucleotide polymorphisms were analyzed to determine lineage and sublineage of isolates. Of 306 isolates genotyped, 246 (80.4%) belonged to the Euro-American lineage, with sublineage 724 predominating at African sites (99/192, 51.5%), and the Euro-American strains other than 724 predominating at non-African sites (89/114, 78.1%). Uneven distribution of lineages across regions limited our ability to discern significant associations, nonetheless, in univariate analyses, Euro-American sublineage 724 was associated with more severe disease at baseline, and along with the East Asian lineage was associated with lower bacteriologic conversion after 8 weeks of treatment. Disease presentation and response to drug treatment varied by lineage, but these associations were no longer statistically significant after adjustment for other variables associated with week-8 culture status.