Cost and cost-effectiveness of BPaL regimen used in drug-resistant TB treatment in the Philippines.

Background: In 2022, the WHO announced that the 6-month BPaL/M regimen should be used for drug-resistant TB (DR-TB). We estimate the patient and provider costs of BPaL compared to current standard-of-care treatment in the Philippines.

Methods: Patients on BPaL under operational research, or 9-11-month standard short oral regimen (SSOR) and 18-21-month standard long oral regimen (SLOR) under programmatic conditions were interviewed using the WHO cross-sectional TB patient cost tool.

Costs of Digital Adherence Technologies for Tuberculosis Treatment Support, 2018-2021.

Digital adherence technologies are increasingly used to support tuberculosis (TB) treatment adherence. Using microcosting, we estimated healthcare system costs (in 2022 US dollars) of 2 digital adherence technologies, 99DOTS medication sleeves and video-observed therapy (VOT), implemented in demonstration projects during 2018-2021. We also obtained cost estimates for standard directly observed therapy (DOT).

Standards for clinical trials for treating TB.

The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice. A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached. Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.

Feasibility and acceptability of asynchronous VOT among patients with MDR-TB.

We conducted a feasibility and acceptability study of video-observed therapy (VOT) among patients with multidrug-resistant TB (MDR-TB) and other types of drug-resistant TB (DR-TB) in the Philippines. Patients aged ≥13 years were approached to use VOT. A smartphone with VOT mobile application to video-record medication intake was provided.

Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial.

Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- ( = 7), 6- to 11- ( = 6), and 3- to 5-year-olds ( = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID).

Implementation of a multidisciplinary antimicrobial stewardship programme in a Philippine tertiary care hospital: an evaluation by repeated point prevalence surveys.

Objectives: Optimising antimicrobial prescribing in hospitals through antimicrobial stewardship (AMS) is essential in addressing the global threat of antimicrobial resistance. The objective of this study was to evaluate the impact of a hospital-wide programme, delivered by a multidisciplinary AMS team, on antimicrobial prescribing outcomes.

Methods: The AMS programme consisted of a combination of persuasive, restrictive, and structural components and was implemented in two phases.

Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans.

Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12 ng/ml) against It is used for the treatment of pulmonary MDR-TB, but pharmacokinetic (PK) data for DLM in the central nervous system (CNS) of patients with TBM are not available.

Lipoarabinomannan in sputum to detect bacterial load and treatment response in patients with pulmonary tuberculosis: Analytic validation and evaluation in two cohorts.

Background: Lipoarabinomannan (LAM) is a major antigen of Mycobacterium tuberculosis (MTB). In this report, we evaluated the ability of a novel immunoassay to measure concentrations of LAM in sputum as a biomarker of bacterial load prior to and during treatment in pulmonary tuberculosis (TB) patients.

Methods And Findings: Phage display technology was used to isolate monoclonal antibodies binding to epitopes unique in LAM from MTB and slow-growing nontuberculous mycobacteria (NTM).

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.

Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016.

Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.

Background: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa.

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors.

Predicting differential rifamycin resistance in clinical Mycobacterium tuberculosis isolates by specific rpoB mutations.

Setting: Rifampin (RMP) resistant Mycobacterium tuberculosis is usually assumed to be resistant to all rifamycins. Increasing evidence indicates, however, that some rpoB mutations, detectable by rapid molecular diagnostics, confer resistance to RMP but not to rifabutin (RBT), suggesting that RBT may be effective for the treatment of M. tuberculosis with these mutations.

Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates.

We report the discovery and confirmation of 23 novel mutations with previously undocumented role in isoniazid (INH) drug resistance, in catalase-peroxidase (katG) gene of Mycobacterium tuberculosis (Mtb) isolates. With these mutations, a synonymous mutation in fabG1 (g609a), and two canonical mutations, we were able to explain 98% of the phenotypic resistance observed in 366 clinical Mtb isolates collected from four high tuberculosis (TB)-burden countries: India, Moldova, Philippines, and South Africa. We conducted overlapping targeted and whole-genome sequencing for variant discovery in all clinical isolates with a variety of INH-resistant phenotypes.

Prognostic significance of novel mutations in tuberculosis.

Background: By using whole genome sequencing (WGS), researchers are beginning to understand the genetic diversity of (MTB) and its consequences for the diagnosis of multidrug-resistant tuberculosis (MDR-TB) on a genomic scale. The Global Consortium for Drug-resistant TB Diagnostics (GCDD) conducted a genome scale variant analyses of 366 clinical MTB genomes (mostly MDR/XDR [extensively drug resistant]) from four countries in order to inform the development of rapid molecular diagnostics. This project has been extended by performing an evolutionary analysis of isoniazid (INH)-resistant isolates for prognostic purposes.

Evaluation of pyrosequencing for detecting extensively drug-resistant Mycobacterium tuberculosis among clinical isolates from four high-burden countries.

Reliable molecular diagnostics, which detect specific mutations associated with drug resistance, are promising technologies for the rapid identification and monitoring of drug resistance in Mycobacterium tuberculosis isolates. Pyrosequencing (PSQ) has the ability to detect mutations associated with first- and second-line anti-tuberculosis (TB) drugs, with the additional advantage of being rapidly adaptable for the identification of new mutations. The aim of this project was to evaluate the performance of PSQ in predicting phenotypic drug resistance in multidrug- and extensively drug-resistant tuberculosis (M/XDR-TB) clinical isolates from India, South Africa, Moldova, and the Philippines.

Predicting extensively drug-resistant Mycobacterium tuberculosis phenotypes with genetic mutations.

Molecular diagnostic methods based on the detection of mutations conferring drug resistance are promising technologies for rapidly detecting multidrug-/extensively drug-resistant tuberculosis (M/XDR TB), but large studies of mutations as markers of resistance are rare. The Global Consortium for Drug-Resistant TB Diagnostics analyzed 417 Mycobacterium tuberculosis isolates from multinational sites with a high prevalence of drug resistance to determine the sensitivities and specificities of mutations associated with M/XDR TB to inform the development of rapid diagnostic methods. We collected M/XDR TB isolates from regions of high TB burden in India, Moldova, the Philippines, and South Africa.

Weight gain and response to treatment for multidrug-resistant tuberculosis.

Alternatives to culture are needed in high burden countries to assess whether response to treatment of multidrug-resistant-tuberculosis (MDR-TB) is satisfactory. The objective was to assess the association of weight gain and treatment outcome. The methods included analysis of clinical, bacteriologic, and weight from 439 MDR-TB patients in the Philippines.

Patterns of treatment interruption among patients with multidrug-resistant TB (MDR TB) and association with interim and final treatment outcomes.

Background: The reasons that patients with multidrug-resistant tuberculosis (MDR TB) miss treatment are multi-factorial and complex. Identifying patterns of treatment interruption that predict poor outcomes can be used to target program activities aiming to improve treatment adherence.

Objective: To characterize patterns of treatment interruption among MDR TB patients and determine the association between patterns and treatment outcomes.

Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study.

Background: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries.

Methods: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand.

Screening outcomes from patients with suspected multidrug-resistant tuberculosis: lessons learned in the Philippines.

Setting: The high prevalence of multidrug-resistant tuberculosis (MDR-TB) in the Philippines is a challenge for the National TB Programme.

Objective: To assess patterns of drug resistance and screening outcomes among MDR-TB suspects evaluated from 2003 to 2008 at DOTS-Plus clinics in the Philippines.

Methods: Descriptive study of 4897 consecutive patients with suspected MDR-TB.

Delamanid for multidrug-resistant pulmonary tuberculosis.

Background: Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.

Methods: In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M.

Impact of patient and program factors on default during treatment of multidrug-resistant tuberculosis.

Setting: In the Philippines, programmatic treatment of drug-resistant tuberculosis (TB) was initiated by the Tropical Disease Foundation in 1999 and transitioned to the National TB Program in 2006.

Objective: To determine patient and socio-demographic characteristics associated with default, and the impact of patient support measures on default.

Design: Retrospective cohort analysis of 583 MDR-TB patients treated from 1999 to 2006.

Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis.

Background: Xpert MTB/RIF (Xpert) is a promising new rapid diagnostic technology for tuberculosis (TB) that has characteristics that suggest large-scale roll-out. However, because the test is expensive, there are concerns among TB program managers and policy makers regarding its affordability for low- and middle-income settings.

Methods And Findings: We estimate the impact of the introduction of Xpert on the costs and cost-effectiveness of TB care using decision analytic modelling, comparing the introduction of Xpert to a base case of smear microscopy and clinical diagnosis in India, South Africa, and Uganda.

Multidrug-resistant tuberculosis among previously treated patients in the Philippines.

Setting: Prior treatment has been associated with multidrug-resistant tuberculosis (MDR-TB) in many settings. The Philippines ranks fifth among 27 priority countries for MDR-TB.

Objective: To determine the rate of MDR-TB among previously treated patients referred for MDR screening and management.