Search

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.

BackgroundStudies in the field of genomic secondary findings (SF) are diverse regarding participants’ characteristics; sequencing methods; versions of the ACMG SF gene list.Aim and methodsBased on whole genome sequencing (WGS) and version 3.1 of ACMG SF list (ACMG SF), we studied SF in 863 individuals from Pakistan: 62% males; 80% had consanguineous parents. In addition to the ACMG SF we have generated a list of gene-disease pairs that have a clear epidemiological and medically actionable value (non-ACMG SF) in Pakistan.ResultsThe total rate of SF was 4.6%, with rates of ACMG SF – 2.7% and non-AGMG SF – 1.9%. 75.0% of ACMG SF were related to cardiovascular diseases (CVD); cancer predisposition syndromes accounted for 16.7%. Among non-ACMG SF 18.8% belong to eye diseases, followed by neuromuscular – 12.5%, metabolic – 12.5%, and urinary system diseases – 12.5%; CVD accounted for 6.3%. We found high proportion of biallelic mutations among both ACMG (4.2%) and non-ACMG (50%) SF.ConclusionsThe frequency of ACMG SF is within the range reported in most studies. High proportion of CVD can be explained by inclusion of additional CVD in the ACMG v3.1 SF list. 1.9% of non-ACMG SF and high proportion of biallelic variants are relevant to epidemiology of Pakistan as a country with high rate of consanguineous marriages. In such countries the ACMG criteria for SF can be expanded, and our list of non-ACMG SF is one example. Our findings may help guide the development of standards of practice in genomic medicine and drive future research.

Concomitant treatment for chronic hepatitis C virus infection and multidrug-resistant tuberculosis is safe and effective.

To address the sub-optimal treatment outcomes among patients with multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the National TB Programme in Belarus started using new drugs such as bedaquiline and delamanid in 2015-16. In this study, we assessed cardiovascular safety and effectiveness (culture conversion, treatment outcomes and post-treatment recurrence) of delamanid-containing regimens among adults (>18 years) with MDR-TB or XDR-TB from June 2016 to February 2018. This was a nationwide cohort study involving analysis of routinely collected programme data from the national and six regional TB hospitals. Cardiovascular adverse events (AEs) were classified as serious or not, based on international guidelines. We conducted Cox proportional hazards regression and calculated adjusted hazards ratio(aHR) and 95% confidence intervals(CI) to evaluate factors associated with AEs and unsuccessful treatment outcomes (death, failure and lost-to-follow-up). Of 125 patients enrolled (35, 28% females; mean age 43 years), 85(68%) had XDR-TB. All the patients received delamanid and 20 patients received both delamanid and bedaquiline. Cardiovascular AEs (177 episodes in total), were observed in the majority (73%) of patients but were mild and managed easily. The most common cardiovascular AEs were QTcF prolongation (64/177, 36%) and other electrocardiography (ECG) abnormalities (40/177, 23%). There were two instances of serious AEs leading to death, both of which were not related to delamanid. In multivariable analysis, male sex (aHR 0.72; 95% CI 0.51-0.99), and baseline ECG abnormalities (aHR 1.68; 95% CI 1.19-2.36) were associated with cardiovascular AEs. Median time to culture conversion was 1.1 months (interquartile range: 1.0-2.1). Culture conversion was observed in 115 (92%) patients at six months of treatment and 110 (88%) completed the treatment successfully. Loss to follow-up, failure and death were observed in 6%, 4% and 2% patients respectively. Among those assessed at 12 months post-treatment (n=33), recurrence was seen in one patient. The only factor associated with unsuccessful treatment outcomes in multivariable analysis was baseline Hepatitis C co-infection (aHR 3.61; 95% CI 1.09-11.95). In conclusion, treatment using delamanid-containing regimens was effective and had a favourable safety profile. We hope our findings inform the development of national clinical guidelines and scale-up of new drugs in other countries.

Background: New and repurposed TB drugs and shorter regimens can radically change the landscape for treating MDR-TB. In December 2019, the WHO issued “Rapid Communication” related to MDR-TB management; WHO reiterated their earlier recommendation that a majority of MDR-TB patients are to receive all-oral treatment regimens, and now allows for shorter duration regimens to be considered under special conditions. Methods: In October 2018 Belarus started to use mSTR for MDR-TB under operational research conditions which include: study protocol; ethics committee review; treatment delivery under WHO-recommended standards. Thirty-nine-week regimen with Lvx, Bdq, Lnz, Cfz and Cs was selected. To be included patients should have laboratory confirmed TB with initial resistance to at least R. Exclusion criteria are: resistance to or previous treatment with any drug of the regimen; QTcF interval longer than 500 msec; ALT/AST more than 5 times higher than upper limits. Results: By 1st February 2020, the programme has included 300 patients. Of them 73 had final treatment outcomes: the median age was 45 years; 79% males; with co-morbidity: HIV - 5%, HCV - 7, DM - 4, Harmful use of alcohol - 15%. The following final treatment outcomes were recorded: treatment success: 67 (91%); lost to follow up: 2 (3%); death: 4 (6%). All deaths were not due to TB or medication. The adverse events were mild and did not prompt the treatment to be stopped. Conclusions: The use of mSTR for MDR-TB under operational research conditions in Belarus shows promising results. The experience gained can promote further expansion of mSTR use to programmatic level.

The TB Portals program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug-resistant tuberculosis working with data scientists and information technology professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), 976 (75.1%) of which are multidrug or extensively drug resistant and 38.2%, 51.9%, and 36.3% of which contain X-ray, computed tomography (CT) scan, and genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and single nucleotide polymorphisms (SNPs) that confer resistance to isoniazid, rifampin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations to our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at https://tbportals.niaid.nih.gov/ .

Multidrug-resistant tuberculosis (mdrtb) refers to TB infection resistant to at least two most powerful anti-TB drugs, isoniazid and rifampincin. It has been estimated that globally 3.5% (which can be much higher in some regions) of newly diagnosed TB patients, and 20.5% of previously treated patients had mdrtb. Extensively drug-resistant TB (xdrtb) has resistance to rifampin and isoniazid, as well as to any member of the quinolone family and at least one of the second line injectable drugs: kanamycin, amikacin and capreomycin. xdrtb accounts for 4-20% of mdrtb. Early detection and targeted treatment are priorities for mdrtb/xdrtb control. The suspicion of mdr/xdr -pulmonary TB (mdrptb or xdrptb) by chest imaging shall suggest intensive diagnostic testing for mdrptb/xdrptb. We hypothesize that multiple nodular consolidation (NC) may serve one of the differentiators for separating dsptb vs mdrptb/xdrptb cases. For this study, mdrptb cases (n=310) and XDR-PTB cases (⋂=I58) were from the NIAID TB Portals Program (TBPP) . Drug sensitive pulmonary TB (dsptb) cases were from the TBPP collection (n=112) as well as the Shenzhen Center for Chronic Disease Control (n=111), Shenzhen, China, and we excluded patients with HIV(+) status. Our study shows NC, particularly multiple NCs, is more common in mdrptb than in dsptb, and more common in xdrptb than in mdrptb. For example, 2.24% of dsptb patients, 13.23% of mdrptb patients, and 20.89% of xdrptb patients, respectively, have NCs with diameter >= 10mm equal or more than 2 in number.

Tuberculosis (TB) is currently the world’s leading cause of infectious mortality. The complex immune response of the human body to Mycobacterium tuberculosis (M.tb) results in a wide array of clinical manifestations, thus the clinical and radiological diagnosis can be challenging. (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) scan with/without computed tomography (CT) component images the whole body and provides a metabolic map of the infection, enabling clinicians to assess the disease burden. (18)F-FDG-PET/CT scan is particularly useful in detecting the disease in previously unknown sites, and allows the most appropriate site of biopsy to be selected. (18)F-FDG-PET/CT is also very valuable in assessing early disease response to therapy, and plays an important role in cases where conventional microbiological methods are unavailable and for monitoring response to therapy in cases of multidrug-resistant TB or extrapulmonary TB. (18)F-FDG-PET/CT cannot reliably differentiate active TB lesion from malignant lesions and false positives can also be due to other infective or inflammatory conditions. (18)F-FDG PET is also unable to distinguish tuberculous lymphadenitis from metastatic lymph node involvement. The lack of specificity is a limitation for (18)F-FDG-PET/CT in TB management.

The Europe Region of the International Union against Tuberculosis and Lung Disease (The Union) held its 7 th Union Europe Conference on Lung Health on 22–24 June 2016 in Bratislava, Slovakia. The conference Patron, the President of the Slovak Republic, Mr. Andrej Kiska, attended the Opening Ceremony and delivered the opening speech. The opening lecture was given by Dr. Mario Raviglione, Director of the Global Tuberculosis Programme of the WHO; he presented the new strategy to fight TB with the aim of ending TB as an epidemic by 2030/35.

Totally implantable central venous access ports (TICVAP) have long been routinely used in cancer chemotherapy. During M/XDR-TB treatment TICVAP can be used in order to avoid daily intramuscular or intravenous injections through peripheral veins over a period of several months. The studies on feasibility and safety of TICVAP in M/XDR-TB treatment are lacking. The aim of the study is to evaluate feasibility and safety of TICVAP use for M/XDR-TB treatment. Patients with confirmed M/XDR-TB who started treatment with regimens containing carbapenems and/or second line injectables were enrolled. TICVAP feasibility was assessed, complications were recorded and analyzed. Between 1 June 2015 and 1 December 2016, 54 TICVAPs were implanted in 52 patients: median age 32 years (range: 14-65); 38(70%) male; 40(74%) previously treated; 5(9%) HIV co-infected. The following veins were used as route: right (34) and left (7) subclavian, right (6) and left (5) jugular; right femoral (2). Seven complications were observed, 5(9%) - required removal, 2(4%) TICVAPs were re-implanted: pneumothorax -1 (pleural tube -1); lumen occlusion -2 (removal -2 and re-implantation -2), pocket and tunnel infection -2 (removal -2), TICVAP-related venous thrombosis -2 (removal -1, anticoagulant therapy -1). All complications were resolved without consequences. Majority of patients 49(94%) and health care practitioners reported advantage of TICVAP over the other types of venous access and intramuscular injections. Conclusions: The study demonstrates high levels of patient acceptability and treatment adherence using TICVAP with reasonable level of safety. The experience gained can promote this approach for further expansion in programmatic settings.

Aim: The aim of this study is to evaluate safety and effectiveness of new and repurposed TB drugs containing regimens in children and adolescents. Methods: Regimens containing bedaquiline, linezolid and clofazimine as backbone drugs were used in children and adolescents with laboratory confirmed M/XDR-TB under the following conditions: careful selection of the patients; Ethic Committee approval and informed consent obtaining; close clinical monitoring; active monitoring and management of adverse events. Results: Between September 2015 and July 2016 15 HIV-negative patients were enrolled in the study: median age 16 years (range: 10-17); 8 males; 10 XDR-TB, 5 pre-XDR-TB of whom 3 with resistance to FQ and 2 – to second line injectables; 5 with cavernous lung lesions on chest X-ray. The treatments continue with median time 11 months (range: 15-6). Adverse events (AE) were developed in all (100%) patients, though they were mild, transient and did not cause drug/regimen stop. The most frequent AE were the following: cQT prolongation, hyperuricemia, hypokalemia, liver function tests elevation, eosinophylia, headache, depression. At six months of treatment 15(100%) patients were sputum smear and culture negative, the negative status continues during further period of monitoring. Conclusion: The study preliminary results show that children and adolescents with M/XDR-TB respond favorably to new and repurposed TB drugs containing regimens confirming their safety and effectiveness.

The emergence and spread of drug-resistant Mycobacterium tuberculosis (DR-TB) are critical global health issues. Eastern Europe has some of the highest incidences of DR-TB, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. To better understand the genetic composition and evolution of MDR- and XDR-TB in the region, we sequenced and analyzed the genomes of 138 M. tuberculosis isolates from 97 patients sampled between 2010 and 2013 in Minsk, Belarus. MDR and XDR-TB isolates were significantly more likely to belong to the Beijing lineage than to the Euro-American lineage, and known resistance-conferring loci accounted for the majority of phenotypic resistance to first- and second-line drugs in MDR and XDR-TB. Using a phylogenomic approach, we estimated that the majority of MDR-TB was due to the recent transmission of already-resistant M. tuberculosis strains rather than repeated de novo evolution of resistance within patients, while XDR-TB was acquired through both routes. Longitudinal sampling of M. tuberculosis from 34 patients with treatment failure showed that most strains persisted genetically unchanged during treatment or acquired resistance to fluoroquinolones. HIV+ patients were significantly more likely to have multiple infections over time than HIV− patients, highlighting a specific need for careful infection control in these patients. These data provide a better understanding of the genomic composition, transmission, and evolution of MDR- and XDR-TB in Belarus and will enable improved diagnostics, treatment protocols, and prognostic decision-making.

There is an urgent need for novel treatments for multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) to improve outcomes. Autologous mesenchymal stromal cell (MSC) infusion is one such possible treatment due to its potential to repair damaged lung tissue and boost the immune response. We analyzed outcome data from 72 M/XDR-TB patients in Belarus that received chemotherapy. Thirty-six patients (“cases”) also had MSCs extracted, cultured and re-infused; the other 36 patients were “study controls”. We identified another control group: 36 patients from the Belarussian surveillance database (“surveillance controls”) matched to cases on drug resistance profile, baseline smear status and previous treatment status. We analyzed culture conversion rates at 2 and 6 months, radiology at baseline and 8 months and final treatment outcomes. Successful outcomes were observed in 81% of cases, 42% of surveillance controls and 39% of study controls. Adjusting for age, odds of a successful outcome was 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 whilst maintaining statistical significance. Cases were less likely (p=0.01) to be culture negative at 2 months than surveillance controls, indicating a poorer initial prognosis in cases before MSC infusion. Radiological improvement was more likely in cases than study controls. Conclusions. MSC treatment could vastly improve outcomes for M/XDR-TB patients. Large, randomized studies are urgently needed to confirm our findings and allow implementation of this treatment.

Summary Background Novel treatment options are urgently needed for multidrug-resistant (MDR) and extensively drugresistant (XDR) tuberculosis, which are associated with immune dysfunction and poor treatment outcomes. Mesenchymal stromal cells (MSCs) are immunomodulatory and adjunct autologous treatment with bone marrowderived MSCs might improve clinical outcome by transforming chronic infl ammation into productive immune responses. Our aim was to assess the safety of infusion of autologous MSCs as an adjunct treatment in patients with tuberculosis. Methods 30 patients with microbiologically confi rmed MDR or XDR tuberculosis were treated with single-dose autologous bone marrow-derived MSCs (aimed for 1 × 10⁶ cells per kg), within 4 weeks of the start of antituberculosisdrug treatment in a specialist centre in Minsk, Belarus. Inclusion patients were those with pulmonary tuberculosis confi rmed by sputum smear microscopy, culture, or both; MDR or XDR tuberculosis confi rmed by drug-susceptibility testing to fi rst-line and second-line drugs; age older than 21 years to 65 years or younger; and absence of lesion compatible with a malignant process or ongoing tuberculosis in organs other than the lungs and pleura. In addition to the inclusion criteria, patients were excluded if they were pregnant, coinfected with HIV, or infected with hepatitis B, C, or both. The primary endpoint was safety measured by MSC-infusion related events; any tuberculosis-related event within the 6 month observation period that related to a worsening of the underlying infectious disease, measured by conversion of Mycobacterium tuberculosis culture or microscopic examination; or any adverse event defi ned clinically or by changes in blood haematology and biochemistry variables, measured monthly for 6 months after MSC infusion per protocol. This study is registered with the German Clinical Trials Registry, number DRKS00000763. Findings The most common (grade 1 or 2) adverse events were high cholesterol levels (14 of 30 patients), nausea (11 of 30 patients), and lymphopenia or diarrhoea (ten of 30 patients). There were no serious adverse events reported. We recorded two grade 3 events that were transitory—ie, increased plasma potassium ion concentrations in one patient and a transitory grade 3 γ-glutamyltransferase elevation in another patient. Interpretation MSCs as an adjunct therapy are safe and can now be explored further for the treatment of patients with MDR or XDR tuberculosis in combination with standard drug regimens. Adjunct treatment with MSCs needs to be evaluated in controlled phase 2 trials to assess eff ects on immune responses and clinical and microbiological outcomes.