Antiretroviral Outcomes in South African Prisoners: A Retrospective Cohort Analysis

Background and Methods: Little is known about antiretroviral therapy (ART) outcomes in prisoners in Africa. We conducted a retrospective review of outcomes of a large cohort of prisoners referred to a public sector, urban HIV clinic. The review included baseline characteristics, sequential CD4 cell counts and viral load results, complications and co-morbidities, mortality and loss to follow-up up to 96 weeks on ART. Findings: 148 inmates (133 male) initiated on ART were included in the study. By week 96 on ART, 73 % of all inmates enrolled in the study and 92 % of those still accessing care had an undetectable viral load (,400copies/ml). The median CD4 cell count increased from 122 cells/mm 3 at baseline to 356 cells/mm 3 by 96 weeks. By study end, 96 (65%) inmates had ever received tuberculosis (TB) therapy with 63 (43%) receiving therapy during the study: 28 % had a history of TB prior to ART initiation, 33 % were on TB therapy at ART initiation and 22 % developed TB whilst on ART. Nine (6%) inmates died, 7 in the second year on ART. Loss to follow-up (LTF) was common: 14 (9%) patients were LTF whilst still incarcerated, 11 (7%) were LTF post-release and 9 (6%) whose movements could not be traced. 16 (11%) inmates had inter-correctional facility transfers and 34 (23%) were released of whom only 23 (68%) returned to the ART clinic for ongoing follow-up. Conclusions: Inmates responded well to ART, despite a high frequency of TB/HIV co-infection. Attention should be directed towards ensuring eligible prisoners access ART programs promptly and that inter-facility transfers and release procedure

The non-clonality of drug resistance in Beijing-genotype isolates of Mycobacterium tuberculosis from the Western Cape of South Africa

Background. The Beijing genotype of M. tuberculosis is a virulent strain that is disseminating worldwide and has a strong association with drug resistance. In the Western Cape of South Africa, epidemiological studies have identified the R220 cluster of the Beijing genotype as a major contributor to a recent outbreak of drug-resistant tuberculosis. Although the outbreak is considered to be due to clonal transmission, the relationship among drug resistant isolates has not yet been established. Results. To better understand the evolution of drug resistance among these strains, 14 drug-resistant clinical isolates of the Beijing genotype were sequenced by whole-genome sequencing, including eight from R220 and six from a more ancestral Beijing cluster, R86, for comparison. While each cluster shares a distinct resistance mutation for isoniazid, mapping of other drug-resistance mutations onto a phylogenetic tree constructed from single nucleotide polymorphisms shows that resistance mutations to many drugs have arisen multiple times independently within each cluster of isolates. Thus, drug resistance among these isolates appears to be acquired, not clonally derived. This observation suggests that, although the Beijing genotype as a whole might have selective advantages enabling its rapid dissemination, the XDR isolates are relatively less fit and do not propagate well. Although it has been hypothesized that the increased frequency of drug resistance in some Beijing lineages might be caused by a mutator phenotype, no significant shift in synonymous substitution patterns is observed in the genomes. Conclusion. While MDR-TB is spreading by transmission in the Western Cape, our data suggests that further drug resistance (i.e. XDR-TB) at this stage is acquired.Peer Reviewe

In-Depth Molecular Characterization of Mycobacterium tuberculosis from New Delhi – Predominance of Drug Resistant Isolates of the ‘Modern’ (TbD1−) Type

BACKGROUND: India has the highest estimated burden of tuberculosis in the world, accounting for 21% of all tuberculosis cases world-wide. However, due to lack of systematic analysis using multiple markers the available information on the genomic diversity of Mycobacterium tuberculosis in India is limited. METHODOLOGY/PRINCIPAL FINDINGS: Thus, 65 M. tuberculosis isolates from New Delhi, India were analyzed by spoligotyping, MIRU-VNTR, large deletion PCR typing and single nucleotide polymorphism analysis (SNP). The Central Asian (CAS) 1 _DELHI sub-lineage was the most prevalent sub-lineage comprising 46.2% (n = 30) of all isolates, with shared-type (ST) 26 being the most dominant genotype comprising 24.6% (n = 16) of all isolates. Other sub-lineages observed were: East-African Indian (EAI)-5 (9.2%, n = 6), EAI6_BGD1 (6.2%, n = 4), EAI3_IND, CAS and T1 with 6.2% each (n = 4 each), Beijing (4.6%, n = 3), CAS2 (3.1%, n = 2), and X1 and X2 with 1 isolate each. Genotyping results from five isolates (7.7%) did not match any existing spoligopatterns, and one isolate, ST124, belonged to an undefined lineage. Twenty-six percent of the isolates belonged to the TbD1+ PGG1 genogroup. SNP analysis of the pncA gene revealed a CAS-lineage specific silent mutation, S65S, which was observed for all CAS-lineage isolates (except two ST26 isolates) and in 1 orphan. Mutations in the pncA gene, conferring resistance to pyrazinamide, were observed in 15.4% of all isolates. Collectively, mutations in the rpoB gene, the katG gene and in both rpoB and katG genes, conferring resistance to rifampicin and isoniazid, respectively, were more frequent in CAS1_DELHI isolates compared to non-CAS_DELHI isolates (OR: 3.1, CI95% [1.11, 8.70], P = 0.045). The increased frequency of drug-resistance could not be linked to the patients' history of previous anti-tuberculosis treatment (OR: 1.156, CI95% [0.40, 3.36], P = 0.79). Fifty-six percent of all new tuberculosis patients had mutations in either the katG gene or the rpoB gene, or in both katG and rpoB genes. CONCLUSION: CAS1_DELHI isolates circulating in New Delhi, India have a high frequency of mutations in the rpoB and katG genes. A silent mutation (S65S) in the pncA gene can be used as a putative genetic marker for CAS-lineage isolates

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP)

Background Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. Methods The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. Discussion If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. Trial registration ISRCTN Registry, ISRCTN92634082. Registered on 31 March 2016

Computational Studies of Binding Energies and Structures of Methylamine on Functionalized Activated Carbon Surfaces

Empirical force fields and density functional theory (DFT) were used to study the binding energies and structures of methylamine on the surface of activated carbon (ACs). This is a first step in studying the adsorption of alkyl amines on the surface of functionalized ACs. The force fields used were Dreiding (DFF), Universal (UFF) and Compass (CFF) models. The generalized gradient approximation with Perdew Wang 91 (PW91) functional was used for DFT calculations. In addition to obtaining the amine-carboxylic acid adsorption energies, the results were used to establish reliability of the empirical models for these systems. CFF predicted a binding energy of (-9.227 kcal/mol) which agreed with PW91 at (-13.17 kcal/mol), compared to DFF (0 kcal/mol) and UFF (-0.72 kcal/mol). However, the CFF binding energies for the amine to ester and ketone disagreed with PW91 results. The structures obtained from all models agreed with PW91 results

Computational Studies of Binding Energies and Structures of Methylamine on Functionalized Activated Carbon Surfaces

Empirical force fields and density functional theory (DFT) were used to study the binding energies and structures of methylamine on the surface of activated carbon (ACs). This is a first step in studying the adsorption of alkyl amines on the surface of functionalized ACs. The force fields used were Dreiding (DFF), Universal (UFF) and Compass (CFF) models. The generalized gradient approximation with Perdew Wang 91 (PW91) functional was used for DFT calculations. In addition to obtaining the amine-carboxylic acid adsorption energies, the results were used to establish reliability of the empirical models for these systems. CFF predicted a binding energy of (-9.227 kcal/mol) which agreed with PW91 at (-13.17 kcal/mol), compared to DFF (0 kcal/mol) and UFF (-0.72 kcal/mol). However, the CFF binding energies for the amine to ester and ketone disagreed with PW91 results. The structures obtained from all models agreed with PW91 results