Is a differentiated care model needed for patients with TB? A cohort analysis of risk factors contributing to unfavourable outcomes among TB patients in two states in South India.

BACKGROUND: TB is a preventable and treatable disease. Yet, successful treatment outcomes at desired levels are elusive in many national TB programs, including India. We aim to identify risk factors for unfavourable outcomes to TB treatment, in order to subsequently design a care model that would improve treatment outcomes among these at-risk patients. METHODS: We conducted a cohort analysis among TB patients who had been recently initiated on treatment. The study was part of the internal program evaluation of a USAID-THALI project, implemented in select towns/cities of Karnataka and Telangana, south India. Community Health Workers (CHWs) under the project, used a pre-designed tool to assess TB patients for potential risks of an unfavourable outcome. CHWs followed up this cohort of patients until treatment outcomes were declared. We extracted treatment outcomes from patient's follow-up data and from the Nikshay portal. The specific cohort of patients included in our study were those whose risk was assessed during July and September, 2018, subsequent to conceptualisation, tool finalisation and CHW training. We used bivariate and multivariate logistic regression to assess each of the individual and combined risks against unfavourable outcomes; death alone, or death, lost to follow up and treatment failure, combined as 'unfavourable outcome'. RESULTS: A significantly higher likelihood of death and experiencing unfavourable outcome was observed for individuals having more than one risk (AOR: 4.19; 95% CI: 2.47-7.11 for death; AOR 2.21; 95% CI: 1.56-3.12 for unfavourable outcome) or only one risk (AOR: 3.28; 95% CI: 2.11-5.10 for death; AOR 1.71; 95% CI: 1.29-2.26 for unfavourable outcome) as compared to TB patients with no identified risk. Male, a lower education status, an initial weight below the national median weight, co-existing HIV, previous history of treatment, drug-resistant TB, and regular alcohol use had significantly higher odds of death and unfavourable outcome, while age > 60 was only associated with higher odds of death. CONCLUSION: A rapid risk assessment at treatment initiation can identify factors that are associated with unfavourable outcomes. TB programs could intensify care and support to these patients, in order to optimise treatment outcomes among TB patients.

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents.

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a-f, 7a-f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20-28.25 µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250 µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.

Mutagenesis of tyrosine and di-leucine motifs in the HIV-1 envelope cytoplasmic domain results in a loss of Env-mediated fusion and infectivity.

BACKGROUND: The gp41 component of the Human Immunodeficiency Virus (HIV) envelope glycoprotein (Env) contains a long cytoplasmic domain (CD) with multiple highly conserved tyrosine (Y) and dileucine (LL) motifs. Studies suggest that the motifs distal to major endocytosis motif (Y712HRL), located at residues 712-715 of Env, may contribute to Env functionality in the viral life cycle. In order to examine the biological contribution of these motifs in the biosynthesis, transport, and function of Env, we constructed two panels of mutants in which the conserved Y- and LL-motifs were sequentially substituted by alternative residues, either in the presence or absence of Y712. Additional mutants targeting individual motifs were then constructed. RESULTS: All mutant Envs, when expressed in the absence of other viral proteins, maintained at least WT levels of Env surface staining by multiple antibodies. The Y712 mutation (Y712C) contributed to at least a 4-fold increase in surface expression for all mutants containing this change. Sequential mutagenesis of the Y- and LL-motifs resulted in a generally progressive decrease in Env fusogenicity. However, additive mutation of dileucine and tyrosine motifs beyond the tyrosine at residue 768 resulted in the most dramatic effects on Env incorporation into virions, viral infectivity, and virus fusion with target cells. CONCLUSIONS: From the studies reported here, we show that mutations of the Y- and LL-motifs, which effectively eliminate the amphipathic nature of the lytic peptide 2 (LLP2) domain or disrupt YW and LL motifs in a region spanning residues 795-803 (YWWNLLQYW), just C-terminal of LLP2, can dramatically interfere with biological functions of HIV-1 Env and abrogate virus replication. Because these mutant proteins are expressed at the cell surface, we conclude that tyrosine and di-leucine residues within the cytoplasmic domain of gp41 play critical roles in HIV-1 replication that are distinct from that of targeting the plasma membrane.