Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Process evaluation for the adaptation, testing and dissemination of a mobile health platform to support people with HIV and tuberculosis in Irkutsk, Siberia.

OBJECTIVES: We developed and tested a mobile health-based programme to enhance integration of HIV and tuberculosis (TB) care and to promote a patient-centred approach in a region of high coinfection burden. Phases of programme development included planning, stakeholder interviews and platform re-build, testing and iteration. SETTING: In Irkutsk, Siberia, HIV/TB coinfection prevalence is high relative to the rest of the Russian Federation. PARTICIPANTS: Pilot testing occurred for a cohort of 60 people with HIV and TB. RESULTS: Key steps emerged to ensure the mobile health-based programme could be operational and adequately adapted for the context, including platform language adaptation, optimisation of server management, iteration of platform features, and organisational practice integration. Pilot testing of the platform rebuild yielded favourable patient perceptions of usability and acceptability at 6 months (n=47 surveyed), with 18 of 20 items showing scores above 4 (on a scale from 1 to 5) on average. Development of this mobile health-based programme for integrated care of infections highlighted the importance of several considerations for tailoring these interventions contextually, including language adaptation and technological capacity, but also, importantly, contextualised patient preferences related to privacy and communication with peers and/or providers, existing regional capacity for care coordination of different comorbidities, and infection severity and treatment requirements. CONCLUSIONS: Our experience demonstrated that integration of care for TB and HIV can be well served by using multimodal mobile health-based programmes, which can enhance communication and streamline workflow between providers across multiple collaborating institutions and improve continuity between inpatient and outpatient care settings. Further study of programme impact on contextual disease-related stigma and social isolation as well as evaluation of implementation on a broader scale for HIV care is currently under way. TRIAL REGISTRATION NUMBER: NCT03819374.

Implementation of a Mobile Health Strategy to Improve Linkage to and Engagement with HIV Care for People Living with HIV, Tuberculosis, and Substance Use in Irkutsk, Siberia.

In Irkutsk, Siberia, there is a high prevalence of HIV and tuberculosis (TB) coinfection. Mobile health (mHealth) strategies have shown promise for increasing linkage to and engagement in care for people living with HIV (PLWH) in other contexts. We evaluated outcomes for a cohort of PLWH, TB, and substance use in Irkutsk after participation in a multi-feature mHealth intervention called MOCT. Sixty patients were enrolled during hospitalization for TB. We evaluated participant app usage, linkage to HIV care postdischarge, perception of self-efficacy related to HIV care, and HIV-related clinical outcomes at 6 months. We also performed an exploratory analysis to compare a subset of 49 patients with a pre-intervention cohort matched for age and gender. Participants demonstrated engagement with app features examined at 6 months. The majority linked to HIV care by 6 months (83%). Self-scoring of confidence in ability to communicate with HIV providers improved from baseline (median score 8, scale 1-10) to 6 months (10, p = 0.004). A higher proportion of the MOCT subset refilled antiretroviral therapy (69% vs. 43% in pre-intervention cohort, p = 0.01), with fewer deaths in the MOCT subset at 6 months (1 death vs. 10 deaths in pre-intervention cohort, p = 0.02) and a decreased likelihood of developing the composite outcome of death/failure to achieve viral suppression at 6 months (adjusted odds ratio = 0.33, p = 0.029). This study demonstrates preliminary intervention uptake and improvement in short-term outcomes for an urban cohort of PLWH, TB, and substance use enrolled in a multi-feature mHealth intervention, a novel strategy for the context. Clinical Trial Registration Number: NCT03819374.

A Geospatial Bibliometric Review of the HIV/AIDS Epidemic in the Russian Federation.

Background: Increasing rates of HIV/AIDS in Eastern Europe and Central Asia contrast global trends, but the scope of HIV/AIDS research originating from Russian Federation and countries of the former Soviet Union has not been quantified. Methods: We searched six major scientific databases in Russian and English languages with medical subject heading terms "HIV" or "AIDS" and "Russia" or "Soviet Union" from 1991 to 2016. Each abstract indexed was reviewed and tagged for 25 HIV/AIDS research themes, location of research focus and first author. Results and Discussion: A total of 2,868 articles were included; 2,156 (75.1%) and 712 (24.8%) described research in the Russian Federation and countries of the former Soviet Union, respectively. There were 15 publications per million population in Russian Federation. Federal districts of the Russian Federation with the highest rates of HIV had the most limited publications. An interactive web-map with time-lapse features and links to primary literature was created using ArcGIS® technology [http://arcg.is/2FUIJ5v]. Conclusion: We found a lower than expected publication rate in the Russian Federation relative to rising HIV prevalence. The greatest deficits were in the most HIV burdened regions in the Russian Federation. Our findings highlight opportunities for new research strategies and public health efforts among key populations and subnational regions.

Response to metronidazole and oxidative stress is mediated through homeostatic regulator HsrA (HP1043) in Helicobacter pylori.

Metronidazole (MTZ) is often used in combination therapies to treat infections caused by the gastric pathogen Helicobacter pylori. Resistance to MTZ results from loss-of-function mutations in genes encoding RdxA and FrxA nitroreductases. MTZ-resistant strains, when cultured at sub-MICs of MTZ (5 to 20 µg/ml), show dose-dependent defects in bacterial growth; depressed activities of many Krebs cycle enzymes, including pyruvate:ferredoxin oxidoreductase (PFOR); and low transcript levels of porGDAB (primer extension), phenotypes consistent with an involvement of a transcriptional regulator. Using a combination of protein purification steps, electrophoretic mobility shift assays (EMSAs), and mass spectrometry analyses of proteins bound to porG promoter sequences, we identified HP1043, an essential homeostatic global regulator (HsrA [for homeostatic stress regulator]). Competition EMSAs and supershift analyses with HsrA-enriched protein fractions confirmed specific binding to porGDAB and hsrA promoter sequences. Exposure to MTZ resulted in >10-fold decreases in levels of HsrA and in levels of the HsrA-regulated gene products PFOR and TlpB. Exposure to paraquat (PQ), hydrogen peroxide, or organic peroxides showed near equivalence with MTZ, revealing a common oxidative stress response pathway. Finally, direct superoxide dismutase (SOD) assays showed an inverse relationship between HsrA levels and SOD activity, suggesting that HsrA may serve as a repressor of sodB. As a homeostatic sentinel, HsrA appears to be ideally positioned to enable rapid shutdown of genes associated with metabolism and growth while activating (directly or indirectly) oxidative defense genes in response to low levels of toxic metabolites (MTZ or oxygen) before they reach DNA-damaging levels.

Mutations to essential orphan response regulator HP1043 of Helicobacter pylori result in growth-stage regulatory defects.

Helicobacter pylori establishes lifelong infections of the gastric mucosa, a niche considered hostile to most microbes. While responses to gastric acidity and local inflammation are understood, little is known as to how they are integrated into homeostatic control of cell division and growth-stage gene expression. Here we investigate the essential orphan response regulator HP1043, a member of the OmpR/PhoB subfamily of transcriptional regulators that is unique to the Epsilonproteobacteria and that lacks phosphorylation domains. To test the hypothesis that conformational changes in the homodimer might lead to defects in gene expression, we sought mutations that might alter DNA-binding efficiency. Two introduced mutations (C215S, C221S) C terminal to the DNA-binding domain of HP1043 (HP1043CC11) resulted in a 2-fold higher affinity for its own promoter by footprinting. Modeling studies with the crystal structure of HP1043 suggested that C215S might affect the helix-turn-helix domain. Genomic replacement of the hp1043 allele with the hp1043CC11 mutant allele resulted in a 2-fold decrease in protein levels, despite a dramatic increase in mRNA. The mutations did not affect in vitro growth rates or colonization efficiency in a mouse model. Proteomic profiling (CC11 mutant strain versus wild type) identified many expression differences, and quantitative PCR further revealed that 11 out of 12 examined genes had lost growth-stage regulation and that 6 of the genes contained HP1043 binding consensus sequences within the promoter regions (fur, cagA, cag23, flhA, flip, and napA). Our studies show that mutations that affect DNA-binding affinity can be used to identify new members of the HP1043 regulon.