Background Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection. Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect. Methods We assessed the performance of Xpert MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF), with fully integrated sample processing in 1730 patients with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis. Eligible patients in Peru, Azerbaijan, South Africa, and India provided three sputum specimens each. Two specimens were processed with N-acetyl-l-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and one specimen was used for direct testing with microscopy and the MTB/RIF test. Results Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive tuberculosis (98.2%) and 124 of 171 with smear-negative tuberculosis (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). Among patients with smear-negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2%. As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria. Sequencing resolved all but two cases in favor of the MTB/RIF assay. Conclusions The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time. (Funded by the Foundation for Innovative New Diagnostics.)

The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)

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...

Background The World Health Organization (WHO) recommends cough as the trigger for tuberculosis (TB) screening in HIV-infected patients, with acid fast bacillus (AFB) smear as the initial diagnostic test. Our objective was to assess the yield and cost of a more intensive TB screening in HIV-infected patients starting antiretroviral therapy (ART) in Durban, South Africa. Methods We prospectively enrolled adults, regardless of TB signs/symptoms, undergoing pre-ART training from May ‘07–May ‘08. Following symptom screen, patients expectorated sputum for AFB smear, TB polymerase chain reaction (PCR), and mycobacterial culture. Sensitivity and specificity of different symptoms and tests, alone and in combination, were compared to a gold standard of 6-week TB culture results. Program costs included personnel, materials and cultures. Results Of 1,035 subjects, 487 (59%) were female; median CD4 count was 100/μl. Two-hundred and ten (20%) were receiving TB treatment and were excluded. Of the remaining 825 subjects, 158 (19%) had positive sputum cultures, of whom 14 (9%) had a positive AFB smear and 82 (52%) reported cough. The combination of cough, other symptoms, AFB smear, and chest x-ray had 93% (CI 88–97%) sensitivity and 15% (CI 13–18%) specificity. The incremental cost of intensive screening including culture was $360/additional TB case identified. Conclusions Nearly 20% of patients starting ART in Durban, South Africa had undiagnosed, culture-positive pulmonary TB. Despite WHO recommendations, neither cough nor AFB smear were adequately sensitive for screening. TB sputum cultures should be performed before ART initiation, regardless of symptoms, in areas of high HIV/TB prevalence.

The COVID-19 pandemic has great potential to disrupt the lives of persons living with HIV (PLWH). The present convergent parallel design mixed-methods study explored the early effects of COVID-19 on African American/Black or Latino (AABL) long-term survivors of HIV in a pandemic epicenter, New York City. A total of 96 AABL PLWH were recruited from a larger study of PLWH with non-suppressed HIV viral load. They engaged in structured assessments focused on knowledge, testing, trust in information sources, and potential emotional, social, and behavioral impacts. Twenty-six of these participants were randomly selected for in-depth semi-structured interviews. Participants were mostly men (64%), African American/Black (75%), and had lived with HIV for 17 years, on average (SD=9 years). Quantitative results revealed high levels of concern about and the adoption of recommended COVID-19 prevention recommendations. HIV care visits were commonly canceled but, overall, engagement in HIV care and antiretroviral therapy use were not seriously disrupted. Trust in local sources of information was higher than trust in various federal sources. Qualitative findings complemented and enriched quantitative results and provided a multifaceted description of both risk factors (e.g., phones/internet access were inadequate for some forms of telehealth) and resilience (e.g., “hustling” for food supplies). Participants drew a direct line between structural racism and the disproportional adverse effects of COVID-19 on communities of color, and their knowledge gleaned from the HIV pandemic was applied to COVID-19. Implications for future crisis preparedness are provided, including how the National HIV/AIDS Strategy can serve as a model to prevent COVID-19 from becoming another pandemic of the poor.