Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model.

BACKGROUND: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB. METHODS: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points. RESULTS: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001). CONCLUSION: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.

Clinical Management of Multidrug-Resistant Tuberculosis in 16 European Countries.

RATIONALE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. OBJECTIVES: To document the management and treatment outcome in patients with MDR-TB in Europe. METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). MEASUREMENTS AND MAIN RESULTS: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%). CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

The TB Portals: an Open-Access, Web-Based Platform for Global Drug-Resistant-Tuberculosis Data Sharing and Analysis.

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 in Europe, 2010-2011.

Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.

LPA or GeneXpert in the diagnosis of multidrug-resistant tuberculosis.

Facing a constant increase of multidrug-resistant tuberculosis (MDR-TB), there is large need for routine use of new diagnostic tests, based on molecular techniques that allow both a rapid diagnosis for TB complex and rapid identification of resistance mutations. The resistances are due to genetic factors: accumulation of changes within the genome structure, acquisition or loss of genes, spontaneous mutations in chromosomal genes, and changes that induce selection of resistant strains during a suboptimal treatment. The bacteriology laboratory plays a crucial role in the making of the diagnosis, monitoring and preventing TB transmission. World Health Organization offers consistent recommendations in favour of use of Xpert MTB/RIF, GeneXpert platform, as initial diagnostic test in adults and children suspected of TB, because it can simultaneously determine the presence of Mycobacterium tuberculosis and the Rifampicin resistance, which is a surrogate marker of MDR strains. The very high sensibility and specificity, also in the smear negative samples, as well as the short time needed for the results, make Xpert MTB/RIF a valuable tool in the fight against TB. Other recommended tests are: LPA, which identifies M. Tuberculosis complex, the Rifancim and Isoniazid resistance; MTBDR plus or, for second line anti-TB drugs, the MTBDRsl.

[Aspects of TB endemia in Romania and the response of the National Programme for Prevention, Surveillance and Control of Tuberculosis]. / Aspecte ale endemiei de tuberculoza in România si raspunsul Programului National de Prevenire, Supraveghere si Control al Tuberculozei (PNPSCT).

In Romania, tuberculosis is a major public health problem. Consistent with the remarkable improvement of success rate in bacteriological confirmed cases from 51% in 1995 to 85.8% in 2011, the global incidence of the disease fell from a maximum of 142.2 per hundred thousand in 2002 to 73.3 per hundred thousand in 2013. The endemia attenuation (so far from historically low in 1985) is highlighted also by the incidence in children and mortality rates. In MDR/XDR TB disease, the situation is significantly different. Although, the endemia intensity is low (500 incident cases and 1,500 prevalent cases) the therapeutic impact is minimum, as demonstrated by the analysis of outcomes. The success rate in the range of 20% is unacceptable in a context of significant issues of legislation and procedures deficiency, with an insufficient funding in which a far too large role returns to external programs, unpredictable and limited as objectives and duration.

[Conventional and molecular diagnosis in a group of patients with drug-resistant tuberculosis]. / Diagnostic conventional si molecular la un esantion de paciensi cu TB-DR.

Worldwide, although the incidence of the sensitive/susceptible tuberculosis diminished, the number of drug resistant tuberculosis is growing. The bacteriological diagnosis, genetic and phenotypic, becomes essential for the epidemic control. The resistance appears as a phenotypic expression of mutations from M. tuberculosis genome. The mutations that appear for Rifampicin are in region rpoB, for Isoniazid in region katG and inhA, for Ethambutol-embB, Quinolone-gyrA, Aminoglicozid and Cyclical Peptides-rrs. To follow the concordance of results of drug sensitivity test (DST) through phenotypic and genetic method, we analyzed a group of 40 patients with TB-DR. We performed drug susceptibility testing on Lowenstein-Jensen medium according to the instructions of the manufacturer. The strains were tested indirect genetic too, Genotype MTBDR plus forl INH and RIF and Genotype MTBDRsl for the second line drugs. The concordance between genetic method and the phenotypic method is 95%, 5% from the patients have different sensitivity to INH and RIF, butphenotypical they are resistant, meaning that they have other mutations undetected by the strip. The most common mutation in region rpoB is MUT3 (52%) associating the absence of band W8. Mutations in the region rpoB MUT1 and MUT2A are 12.5%, and 15% respectively. For high resistance to INH, the mostcommon isMUT1 forkatG 95% and forlow resistance to INHMUTI from region inhA-30%. For the second line drugs, the most frequent concordance between genetic method andphenotypic method is for EMB, of 30%, geneticallyspeaking the strains display no mutation in region embB, but are resistantin phenotypic method. For FQ, KAN, AMKand CAP the concordance between the two methods is of 100% to all tested strains. In conclusion, genetic methods have high sensitivity, they are fast and shorten significantly the diagnosis time.