Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

H3Africa is developing capacity for health-related genomics research in Africa

BACKGROUND Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants’ history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment– length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log 10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log 10 CFU counts (؎ standard deviation) from baseline to day 7 were 0.04 ؎ 0.46 for 25 mg TMC207 (n ‫؍‬ 14), 0.26 ؎ 0.64 for 100 mg TMC207 (n ‫؍‬ 14), 0.77 ؎ 0.58 for 400 mg TMC207 (n ‫؍‬ 14), 1.88 ؎ 0.74 for INH (n ‫؍‬ 11), and 1.70 ؎ 0.71 for RIF (n ‫؍‬ 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.Tuberculosis (TB) has reemerged as one of the most deadly infectious diseases worldwide, killing approximately 1.7 million people in 2004 (25). In Africa, more than 30% of new adult TB cases are coinfected with human immunodeficiency virus (HIV) (5). Widespread efforts to control the resurgence of TB, such as the implementation of outcome-driven treatment programs (16) and the introduction of "directly observed therapy short-course" (26), have had limited success, in part due to constrained public health resources and the length of treatment needed to sterilize infectious TB lesions. The global situation is deteriorating further with the spread of multidrugresistant (MDR) TB (7, 8) and, more recently, extensively drug-resistant TB (9). There is an urgent need for new anti-TB agents that can shorten treatment duration and are effective in treating drug-sensitive, drug-resistant, and latent TB infection (22).Tibotec Medicinal Compound 207 (TMC207) (also known as R207910) belongs to a newly identified chemical class with antimycobacterial properties. TMC207 demonstrates unique and specific antimycobacterial activity by inhibiting the oligomeric and proteolipic subunit c of mycobacterial ATP synthase, a critical enzyme in the synthesis of ATP (17). Binding of TMC207 to subunit c leads to inhibition of ATP synthesis, which subsequently results in bacterial death. In vitro mycobacterial susceptibility experimen...