Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

Predictors of weight loss during the intensive phase of tuberculosis treatment in patients with drug-susceptible pulmonary tuberculosis in South India.

BACKGROUND: Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes. There is limited description of weight loss and its predictors during intensive treatment phase. The objective of this study was to assess the predictors of weight loss during intensive phase and to see if there is any association exists with sputum conversion at the end of intensive phase of treatment. METHODS: Data collected as a part of the prospective TB cohort (Regional Prospective Observational Research for TB India Phase 1) conducted in Pondicherry, Cuddalore and Viluppuram districts of Tamil Nadu were used for this study. Sputum smear and body weight comparison were made in the baseline and at the end of second month of treatment. RESULTS: In all, 726 participants had weight measurements at the two time points and 18.7% had weight loss; mean weight lost being 2.3 kg (SD 3.05). Mean weight loss was more among males (2.4 kg, SD 3.2), diabetics (2.8 kg, SD 3.9) and alcoholics (2.1 kg, SD 2.4). Alcohol consumption was the only predictor of weight loss after adjusting for age, diabetes, marital status and BMI (aRR 1.52, P 0.02). Weight loss was not associated with sputum conversion at the end of second month. CONCLUSIONS: Alcohol use emerged as the major predictor for weight loss during intensive phase.

Development and Validation of a Parsimonious Tuberculosis Gene Signature Using the digital NanoString nCounter Platform.

BACKGROUND: Blood-based biomarkers for diagnosing active tuberculosis (TB), monitoring treatment response, and predicting risk of progression to TB disease have been reported. However, validation of the biomarkers across multiple independent cohorts is scarce. A robust platform to validate TB biomarkers in different populations with clinical end points is essential to the development of a point-of-care clinical test. NanoString nCounter technology is an amplification-free digital detection platform that directly measures mRNA transcripts with high specificity. Here, we determined whether NanoString could serve as a platform for extensive validation of candidate TB biomarkers. METHODS: The NanoString platform was used for performance evaluation of existing TB gene signatures in a cohort in which signatures were previously evaluated on an RNA-seq dataset. A NanoString codeset that probes 107 genes comprising 12 TB signatures and 6 housekeeping genes (NS-TB107) was developed and applied to total RNA derived from whole blood samples of TB patients and individuals with latent TB infection (LTBI) from South India. The TBSignatureProfiler tool was used to score samples for each signature. An ensemble of machine learning algorithms was used to derive a parsimonious biomarker. RESULTS: Gene signatures present in NS-TB107 had statistically significant discriminative power for segregating TB from LTBI. Further analysis of the data yielded a NanoString 6-gene set (NANO6) that when tested on 10 published datasets was highly diagnostic for active TB. CONCLUSIONS: The NanoString nCounter system provides a robust platform for validating existing TB biomarkers and deriving a parsimonious gene signature with enhanced diagnostic performance.

Directly Observed Therapy to Measure Adherence to Tuberculosis Medication in Observational Research: Protocol for a Prospective Cohort Study.

BACKGROUND: A major challenge for prospective, clinical tuberculosis (TB) research is accurately defining a metric for measuring medication adherence. OBJECTIVE: We aimed to design a method to capture directly observed therapy (DOT) via mobile health carried out by community workers. The program was created specifically to measure TB medication adherence for a prospective TB cohort in Western Cape Province, South Africa. METHODS: Community workers collect daily adherence data on mobile smartphones. Participant-level adherence, program-level adherence, and program function are systematically monitored to assess DOT program implementation. A data dashboard allows for regular visualization of indicators. Numerous design elements aim to prevent or limit data falsification and ensure study data integrity. RESULTS: The cohort study is ongoing and data collection is in progress. Enrollment began on May 16, 2017, and as of January 12, 2021, a total of 236 participants were enrolled. Adherence data will be used to analyze the study's primary aims and to investigate adherence as a primary outcome. CONCLUSIONS: The DOT program includes a mobile health application for data collection as well as a monitoring framework and dashboard. This approach has potential to be adapted for other settings to improve the capture of medication adherence in clinical TB research. TRIAL REGISTRATION: Clinicaltrials.gov NCT02840877; https://clinicaltrials.gov/ct2/show/NCT02840877.

Using Cure Models to Estimate the Serial Interval of Tuberculosis With Limited Follow-up.

Serial interval (SI), defined as the time between symptom onset in an infector and infectee pair, is commonly used to understand infectious diseases transmission. Slow progression to active disease, as well as the small percentage of individuals who will eventually develop active disease, complicate the estimation of the SI for tuberculosis (TB). In this paper, we showed via simulation studies that when there is credible information on the percentage of those who will develop TB disease following infection, a cure model, first introduced by Boag in 1949, should be used to estimate the SI for TB. This model includes a parameter in the likelihood function to account for the study population being composed of those who will have the event of interest and those who will never have the event. We estimated the SI for TB to be approximately 0.5 years for the United States and Canada (January 2002 to December 2006) and approximately 2.0 years for Brazil (March 2008 to June 2012), which might imply a higher occurrence of reinfection TB in a developing country like Brazil.

Latent Tuberculosis Infection Testing Practices in Long-Term Care Facilities, Boston, Massachusetts.

OBJECTIVES: To describe latent tuberculosis infection (LTBI) testing practices in long-term care facilities (LTCFs). DESIGN: Retrospective cohort study. SETTING: Three Boston-area LTCFs. PARTICIPANTS: Residents admitted between January 1 and December 31, 2011. MEASUREMENTS: Resident demographic characteristics, comorbidities, LTCF stay, and LTBI testing and treatment. RESULTS: Data for 291 LTCF residents admitted in 2011 were reviewed. Of the 257 without a history of LTBI and with documentation of testing, 162 (63%) were tested; 114 of 186 (61%) with a stay less than 90 days and 48 of 71 (68%) with a stay of 90 days or longer were tested. Of 196 residents with data on prior LTBI testing, 39 (19.9%) had LTBI; 12 of these (30.8%) were diagnosed at the LTCF. Hispanic participants were more likely than black participants to undergo LTBI testing (adjusted odds ratio (aOR) = 2.4, P = .003). Having a length of stay of less than 90 days (aOR = 0.7, P < .001) and history of illicit drug use (aOR = 0.7, P < .001) were associated with lower odds of LTBI testing. CONCLUSION: One-fifth of LTCF residents had LTBI, but testing was not always performed. The high prevalence of LTBI in older adults combined with the risk of an outbreak if a case of tuberculosis occurs in a LTCF make LTBI testing and treatment an important prevention opportunity. The importance of LTBI testing in LTCFs needs to be reinforced.

Increased risk of active tuberculosis after cancer diagnosis.

BACKGROUND: Cancer may increase risk of active tuberculosis but evidence is sparse. We therefore examined tuberculosis risk in patients with incident cancer using Danish nationwide medical databases. METHODS: We conducted a matched follow-up study comparing risk of active tuberculosis in cancer-exposed individuals to that in a general population comparison cohort, matched on gender, age, and country of origin, in different follow-up intervals using Cox regression. FINDINGS: We identified 290,944 patients with incident cancer and 871,147 matched comparison cohort members during 1 January, 2004-30 November, 2013. After adjusting for comorbidities, the overall adjusted hazard ratio (aHR) for tuberculosis among cancer patients was 2.48 (95% confidence interval [CI]: 1.99-3.10). The highest tuberculosis risks were observed following cancers of the aerodigestive tract (aHR = 8.12; 95% CI: 4.33-15.22), tobacco-related cancers (aHR = 5.01; 95% CI: 3.37-7.44), and hematological cancers (aHR = 4.88; 95% CI: 2.27-10.48). Tuberculosis risk was highly elevated within the first year after cancer diagnosis (aHR = 4.14; 95% CI: 2.88-5.96), with a 6.78-fold increased aHR for cancer patients receiving cytostatics or radiotherapy. Beyond five years of observation, the overall aHR for tuberculosis remained at 2.66 (95% CI: 1.22-5.81). INTERPRETATION: Cancer is a clinical predictor for increased risk of active tuberculosis, probably related to decreased infection barriers, immunosuppression, and shared risk factors.

Risk factors for postoperative pneumonia after lung cancer surgery and impact of pneumonia on survival.

OBJECTIVE: Little is known about risk factors and prognosis for postoperative pneumonia (POP) in patients undergoing therapeutic lung cancer (LC) surgery. METHODS: We followed a nationwide population-based cohort of 7479 patients with LC surgery in Denmark 1995-2011. We used logistic regression analysis to examine risk factors for POP within 30 days after surgery. Subsequent survival in patients with POP was analyzed with Cox regression. RESULTS: We identified 268 (3.6%) patients with POP. Important risk factors included advanced age (age ≥80 years: (adjusted odds ratio [aOR] = 3.64; 95% CI: 2.17-6.12) as compared to patients aged 50-59 years), previous pneumonia (aOR = 2.68; 95% CI: 2.02-3.56), obesity (aOR = 1.91; 95% CI: 0.99-3.69), chronic pulmonary disease (aOR = 1.90; 95% CI: 1.40-2.57), alcoholism (aOR = 1.56; 95% CI: 0.81-3.01), and atrial fibrillation (aOR = 1.42; 95% CI: 0.82-2.45). Overall thoracoscopic surgery halved the risk of POP and the highest risk of POP was seen in pneumonectomy performed in open thoracotomy. Among patients surviving the 30-day postoperative period, 31-365 day mortality was 21.6% in POP patients vs. 16.8% in non-POP patients, and 1-5-year mortality was 62.2% vs. 53.0%. Adjusted 31-365 day hazard ratio (HR) of death with POP was 1.31 (95% CI: 1.00-1.73), and 1-5 year HR was 1.22 (95% CI 0.98-1.53). CONCLUSION: Major risk factors for POP following LC surgery are advanced age, previous pneumonia, obesity, chronic pulmonary disease, alcoholism, and atrial fibrillation. POP is a clinical marker for decreased LC survival.

The cost-effectiveness of improved hepatitis C virus therapies in HIV/hepatitis C virus coinfected patients.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of strategies to treat hepatitis C virus (HCV) in HIV/HCV coinfected patients in the United States. PARTICIPANTS: Simulated cohort of HIV/HCV genotype 1 coinfected, noncirrhotic, HCV treatment-naive individuals enrolled in US HIV guideline-concordant care. DESIGN/INTERVENTIONS: Monte Carlo simulation comparing five strategies: no treatment; dual therapy with pegylated-interferon (PEG) and ribavirin (RBV); 'PEG/RBV trial' in which all patients initiate dual therapy and switch to triple therapy upon failure; 'IL28B triage' in which patients initiate either dual therapy or triple therapy based on their IL28B allele type; and PEG/RBV and telaprevir (TPV) triple therapy. Sensitivity analyses varied efficacies and costs and included a scenario with interferon (IFN)-free therapy. MAIN MEASURES: Sustained virologic response (SVR), life expectancy, discounted quality-adjusted life expectancy (QALE), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs) in $/quality-adjusted life years (QALY) gained. RESULTS: 'PEG/RBV trial,' 'IL28B triage,' and 'triple therapy' each provided 72% SVR and extended QALE compared with 'dual therapy' by 1.12, 1.14, and 1.15 QALY, respectively. The ICER of 'PEG/RBV trial' compared with 'dual therapy' was $37 500/QALY. 'IL28B triage' and 'triple therapy' provided little benefit compared with 'PEG/RBV trial,' and both had ICERs exceeding $300 000/QALY. In sensitivity analyses, IFN-free treatment attaining 90% SVR had an ICER less than $100 000/QALY compared with 'PEG/RBV trial' when its cost was $109 000 or less (125% of the cost of PEG/RBV/TVR). CONCLUSION: HCV protease inhibitors are most efficiently used in HIV/HCV coinfection after a trial of PEG/RBV, sparing protease inhibitors for those who attain rapid virologic response and SVR. The cost-effectiveness of IFN-free regimens for HIV/HCV coinfection will depend on the cost of these therapies.

High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers.

BACKGROUND: Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS: Hospital admission rates and hospital admission incidence rate ratios. RESULTS: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.

OBJECTIVE: To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis. DESIGN AND METHODS: The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints). RESULTS: Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events. CONCLUSION: Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.