Effectiveness of a novel cellular therapy to treat multidrug-resistant tuberculosis

AbstractBackground/objectiveWe urgently need novel treatments for multidrug-resistant tuberculosis (MDR-TB). Autologous mesenchymal stromal cell (MSC) infusion is one such possibility due to its potential to repair damaged lung tissue and boost immune responses. We aimed to assess the safety and effectiveness of MSC to improve treatment outcomes among MDR-TB patients.MethodsWe analyzed treatment outcomes for 108 Belarusian MDR-TB patients receiving chemotherapy. Thirty-six patients (cases) also had MSCs collected, extracted, cultured, and reinfused (average time from chemotherapy start to infusion was 49days) in optimal dose; another 36 patients (without MSC treatment) were “study controls”. We identified another control group: 36 patients from the Belarusian national surveillance database (surveillance controls) 1:1 matched to cases.ResultsSuccessful outcomes were observed in 81% of cases, 42% of surveillance controls, and 39% of study controls. After adjusting for age, odds of a successful outcome were 6.5 (95% confidence interval, 1.2–36.2, p=0.032) times greater for cases than surveillance controls. Adjusting for other potential confounders increased the effect estimate while maintaining statistical significance. Cases were less likely (p=0.01) to be culture negative at 2months than surveillance controls, indicating a poorer initial prognosis in cases before (or shortly after) infusion. Radiological improvement was more likely in cases than in study controls.ConclusionMSC treatment could vastly improve treatment outcomes for MDR-TB patients. Our findings could revolutionize therapy options and have strong implications for future directions of MDR-TB therapy researc

Optima TB: A tool to help optimally allocate tuberculosis spending

Approximately 85% of tuberculosis (TB) related deaths occur in low- and middle-income countries where health resources are scarce. Effective priority setting is required to maximise the impact of limited budgets. The Optima TB tool has been developed to support analytical capacity and inform evidence-based priority setting processes for TB health benefits package design. This paper outlines the Optima TB framework and how it was applied in Belarus, an upper-middle income country in Eastern Europe with a relatively high burden of TB. Optima TB is a population-based disease transmission model, with programmatic cost functions and an optimisation algorithm. Modelled populations include age-differentiated general populations and higher-risk populations such as people living with HIV. Populations and prospective interventions are defined in consultation with local stakeholders. In partnership with the latter, demographic, epidemiological, programmatic, as well as cost and spending data for these populations and interventions are then collated. An optimisation analysis of TB spending was conducted in Belarus, using program objectives and constraints defined in collaboration with local stakeholders, which included experts, decision makers, funders and organisations involved in service delivery, support and technical assistance. These analyses show that it is possible to improve health impact by redistributing current TB spending in Belarus. Specifically, shifting funding from inpatient- to outpatient-focused care models, and from mass screening to active case finding strategies, could reduce TB prevalence and mortality by up to 45% and 50%, respectively, by 2035. In addition, an optimised allocation of TB spending could lead to a reduction in drug-resistant TB infections by 40% over this period. This would support progress towards national TB targets without additional financial resources. The case study in Belarus demonstrates how reallocations of spending across existing and new interventions could have a substantial impact on TB outcomes. This highlights the potential for Optima TB and similar modelling tools to support evidence-based priority setting

Tuberculosis Drug Susceptibility, Treatment, and Outcomes for Belarusian HIV-Positive Patients with Tuberculosis: Results from a National and International Laboratory

Background. To cure drug-resistant (DR) tuberculosis (TB), the antituberculous treatment should be guided by Mycobacterium tuberculosis drug-susceptibility testing (DST). In this study, we compared conventional DST performed in Minsk, Belarus, a TB DR high-burden country, with extensive geno- and phenotypic analyses performed at the WHO TB Supranational Reference Laboratory in Copenhagen, Denmark, for TB/HIV coinfected patients. Subsequently, DST results were related to treatment regimen and outcome. Methods. Thirty TB/HIV coinfected patients from Minsk were included and descriptive statistics applied. Results. Based on results from Minsk, 10 (33%) TB/HIV patients had drug-sensitive TB. Two (7%) had isoniazid monoresistant TB, 8 (27%) had multidrug-resistant (MDR) TB, 5 (17%) preextensive drug-resistant (preXDR) TB, and 5 (17%) had extensive drug-resistant (XDR) TB. For the first-line drugs rifampicin and isoniazid, there was DST agreement between Minsk and Copenhagen for 90% patients. For the second-line anti-TB drugs, discrepancies were more pronounced. For 14 (47%) patients, there were disagreements for at least one drug, and 4 (13%) patients were classified as having MDR-TB in Minsk but were classified as having preXDR-TB based on DST results in Copenhagen. Initially, all patients received standard anti-TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol. However, this was only suitable for 40% of the patients based on DST. On average, DR-TB patients were changed to 4 (IQR 3-5) active drugs after 1.5 months (IQR 1-2). After treatment adjustment, the treatment duration was 8 months (IQR 2-11). Four (22%) patients with DR-TB received treatment for >18 months. In total, sixteen (53%) patients died during 24 months of follow-up. Conclusions. We found high concordance for rifampicin and isoniazid DST between the Minsk and Copenhagen laboratories, whereas discrepancies for second-line drugs were more pronounced. For patients with DR-TB, treatment was often insufficient and relevant adjustments delayed. This example from Minsk, Belarus, underlines two crucial points in the management of DR-TB: the urgent need for implementation of rapid molecular DSTs and availability of second-line drugs in all DR-TB high-burden settings. Carefully designed individualized treatment regimens in accordance with DST patterns will likely improve patients’ outcome and reduce transmission with drug-resistant Mycobacterium tuberculosis strains

Multidrug-resistant tuberculosis in Belarus: the size of the problem and associated risk factors

OBJECTIVE: To assess the problem of multidrug-resistant tuberculosis (MDR-TB) throughout Belarus and investigate the associated risk factors. METHODS: In a nationwide survey in 2010-2011, 1420 tuberculosis (TB) patients were screened and 934 new and 410 previously treated cases ofTB were found to meet the inclusion criteria. Isolates of Mycobacterium tuberculosis from each eligible patient were tested for susceptibility to anti-TB drugs. Sociobehavioural information was gathered in interviews based on a structured questionnaire. FINDINGS: MDR-TB was found in 32.3% and 75.6% of the new and previously treated patients, respectively, and, 11.9% of the 612 patients found to have MDR-TB had extensively drug-resistant TB (XDR-TB). A history of previous treatment for TB was the strongest independent risk factor for MDR-TB (odds ratio, OR: 6.1; 95% confidence interval, CI: 4.8-7.7). The other independent risk factors were human immunodeficiency virus (HIV) infection (OR: 2.2; 95% CI: 1.4-3.5), age < 35 years (OR: 1.4; 95% CI: 1.0-1.8), history of imprisonment (OR: 1.5; 95% CI: 1.1-2.0), disability sufficient to prevent work (OR: 1.9; 95% CI: 1.2-3.0), alcohol abuse (OR: 1.3; 95% CI: 1.0-1.8) and smoking (OR: 1.5; 95% CI: 1.1-2.0). CONCLUSION: MDR-TB is very common among TB patients throughout Belarus. The numerous risk factors identified for MDR-TB and the convergence of the epidemics of MDR-TB and HIV infection call not only for stronger collaboration between TB and HIV control programmes, but also for the implementation of innovative measures to accelerate the detection of TB resistance and improve treatment adherence