Shorter TB treatment regimens should be safer as well.
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ABSTRACT:
SUBMITTER: Rucsineanu O
PROVIDER: S-EPMC10446660 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Shorter TB treatment regimens should be safer as well.
Rucsineanu O O Agbassi P P Herrera R R Low M M McKenna L L Stillo J J Winarni P P Acharya A A Sari A H AH
Public health action 20230901 3
Most ongoing and planned TB therapeutic trials are focused on shortening the duration of treatment while giving less consideration to other aspects of TB care that are important to people with TB. Here we argue that other variables besides duration of TB treatment should also be considered when developing new TB treatment regimens, including drug toxicity, time spent in monitoring and overall quality of life while on therapy. We examine the specific use of linezolid in treatment-shortening trial ...[more]
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| S-EPMC9221684 | biostudies-literature
Project description:Tools for effective TB control have been available for years. Case finding, active medications, case management and directly observed therapy are the foundations for the management of TB. The current TB epidemic, centered in resource-limited settings is fueled by the HIV-1 epidemic. Lack of ability to diagnose and treat drug-resistant TB has led to development of more extensive patterns of resistance. Among the currently available drugs, there is reason to hope that rifamycins paired with fluoroquinolones will lead to shorter treatment regimens for drug-susceptible TB. As the result of novel public-private collaborations and investments of resources, new drugs are being developed. These include TMC207, already shown to have activity early in the treatment of multidrug-resistant TB and others that are likely to be active against persistor organisms, and have the prospect to dramatically shorten treatment courses for active and latent TB. Given that these drugs have novel mechanisms of action, combinations have the prospect to be highly active even against multidrug-resistant organisms.
| S-EPMC3647464 | biostudies-literature
Project description:BACKGROUND: The implementation of tuberculosis preventive treatment (TPT) is challenging especially in resource-limited settings. As part of a Phase 3 trial on TPT, we described our experience with the use of rifampicin for 4 months (4R) and isoniazid for 9 months (9H) in Indonesia.METHODS: In 2011-2017, children and adults with latent TB infection were randomised to either 4R or 9H and followed until 16 months after randomisation for children and 28 months for adults. The primary outcome was the treatment completion rate. Secondary outcomes were Grade 3-5 adverse events (AEs), active TB occurrence, and health costs.RESULTS: A total of 157 children and 860 adults were enrolled. The 4R treatment completion rate was significantly higher than that of 9H (78.7% vs. 65.5%), for a rate difference of 13.2% (95% CI 7.1-19.2). No Grade 3-5 AEs were reported in children; in adults, it was lower in 4R (0.4%) compared to 9H (2.8%). The incidence of active TB was lower with 4R than with 9H (0.09/100 person-year vs. 0.36/100 person-year) (rate difference: -0.36/100 person-year). The total cost per patient was lower for the 4R regimen than for the 9H regimen (USD151.9 vs. USD179.4 in adults and USD152.9 vs. USD206.5 in children)CONCLUSIONS: Completion and efficacy rates for 4R were better than for 9H. Compared to 9H, 4R was cheaper in all age groups, safer in adults and equally safe in children. The Indonesian TB program could benefit from these benefits of the 4R regimen.
| S-EPMC8802562 | biostudies-literature
Project description:BackgroundMultidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification.MethodsTB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total).DiscussionRapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs.Trail registrationClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.
| S-EPMC7888137 | biostudies-literature
Project description:Purpose of reviewDespite broad uptake of antiretroviral therapy (ART), tuberculosis (TB) incidence and mortality among people with HIV remain unacceptably high. Short-course regimens for TB, incorporating both novel and established drugs, offer the potential to enhance adherence and completion rates, thereby reducing the global TB burden. This review will outline short-course regimens for TB among patients with HIV.Recent findingsAfter many years without new agents, there is now active testing of many novel drugs to treat TB, both for latent infection and active disease. Though not all studies have included patients with HIV, many have, and there are ongoing trials to address key implementation challenges such as potent drug-drug interactions with ART. The goal of short-course regimens for TB is to enhance treatment completion without compromising efficacy. Particularly among patients with HIV, studying these shortened regimens and integrating them into clinical care are of urgent importance. There are now multiple short-course regimens for latent infection and active disease that are safe and effective among patients with HIV.
| S-EPMC9178518 | biostudies-literature
Project description:BackgroundDirect acting antiviral hepatitis C virus (HCV) therapies are highly effective but costly. Wider adoption of an 8-week ledipasvir/sofosbuvir treatment regimen could result in significant savings, but may be less efficacious compared with a 12-week regimen. We evaluated outcomes under a constrained budget and cost-effectiveness of 8 vs 12 weeks of therapy in treatment-naïve, noncirrhotic, genotype 1 HCV-infected black and nonblack individuals and considered scenarios of IL28B and NS5A resistance testing to determine treatment duration in sensitivity analyses.MethodsWe developed a decision tree to use in conjunction with Monte Carlo simulation to investigate the cost-effectiveness of recommended treatment durations and the population health effect of these strategies given a constrained budget. Outcomes included the total number of individuals treated and attaining sustained virologic response (SVR) given a constrained budget and incremental cost-effectiveness ratios.ResultsWe found that treating eligible (treatment-naïve, noncirrhotic, HCV-RNA <6 million copies) individuals with 8 weeks rather than 12 weeks of therapy was cost-effective and allowed for 50% more individuals to attain SVR given a constrained budget among both black and nonblack individuals, and our results suggested that NS5A resistance testing is cost-effective.ConclusionsEight-week therapy provides good value, and wider adoption of shorter treatment could allow more individuals to attain SVR on the population level given a constrained budget. This analysis provides an evidence base to justify movement of the 8-week regimen to the preferred regimen list for appropriate patients in the HCV treatment guidelines and suggests expanding that recommendation to black patients in settings where cost and relapse trade-offs are considered.
| S-EPMC5767946 | biostudies-literature
Project description:IntroductionPeople living with multidrug-resistant tuberculosis currently have few options for effective treatment and cure. Regimens that are available are toxic, may involve injections and take up to 2 years to complete treatment, with success rates as low as 50%. The TB-PRACTECAL trial is evaluating shorter, more tolerable regimens of oral drugs; we detail the substudy within this trial, PRACTECAL-PRO, which aims to evaluate patient experiences and perspectives on treatment, to understand outcomes more fully.Methods and analysisWe are conducting a mixed-methods evaluation within both investigational and standard of care arms within the TB-PRACTECAL trial, using sequential quality of life (QoL) surveys and in-depth interviews. Data collection involves the Short Form 12 (SF-12) and St George's Respiratory Questionnaire (SGRQ), collected at up to four fixed timepoints, from baseline, to up to 12 months later. Healthy volunteers will be surveyed to establish locally relevant controls. We will also purposively sample participants for qualitative data collection and analysis, to provide rich explanation of QoL scores. The study will be implemented in all six TB-PRACTECAL study sites in Uzbekistan, South Africa and Belarus. QoL surveys will be scored and analysed according to SF-12 and SGRQ developers' manuals. Differences between scores at baseline and later timepoints will be evaluated as well as graphical exploration of group score trajectories of investigational and standard of care arms.Ethics and disseminationEthics approval was obtained from the Médecins Sans Frontières Ethics Review Board. Local ethics approval has been obtained in Uzbekistan, Belarus and South Africa. Results of the substudy will be shared with local health authorities, the WHO and submitted for publication in a peer-reviewed journal.Trial registration numberNCT03942354; Pre-results.
| S-EPMC8422308 | biostudies-literature
Project description:BACKGROUND:Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. METHODS/DESIGN:SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. DISCUSSION:Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. TRIAL REGISTRATION:International Standard Randomised Controlled Trials Number: ISRCTN63579542 , 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379 , 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.
| S-EPMC5909210 | biostudies-literature
Project description:BackgroundAt a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens.MethodsThis is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries.DiscussionThe endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments.Trial registrationThis study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).
| S-EPMC6701145 | biostudies-literature
Project description:Background and aimsMulti drug or rifampicin resistant tuberculosis (MDR/RR-TB) is a major burden to TB prevention and eradication globally. Since 2016, WHO guidelines have included options for treating MDR/RR-TB with a standard regimen of 9 to 11 months duration (the 'shorter regimen') rather than an individual regimen of at least 20 months. This regimen has been introduced in Indonesia since September 2017. Therefore, we aimed to determine the success rate and factors associated with the treatment outcome of shorter injectable based regimen in West Java province, Indonesia.MethodsThis was a retrospective cohort study of MDR/RR-TB patients aged over 18 years old who received the shorter injectable based regimen between September 2017 and December 2020. We defined successful outcomes as the combined proportion of patients who were cured or had complete treatment. While, unsuccessful outcomes were defined as the combined proportion of patients who died from any causes, failure, and loss to follow-up (LTFU).ResultsA total of 315 patients were included in this study. The success rate was 64.5%. Multivariate analysis showed male gender (aRR = 1.18, 95% CI 1.04 to 1.34) increased the chance of successful outcome, while malnutrition (aRR = 0.78, 95% CI 0.68 to 0.89), history of previous TB treatment (aRR = 0.80%CI 0.68 to 0.94), and time of culture conversion >2 months (aRR = 0.72 (95% CI 0.59 to 0.87) decreased the chance of successful outcome.ConclusionHistory of previous TB treatment, time of culture conversion >2 months, and malnutrition were independent factors that decrease the chance for success rate, while male gender increase the likelihood for success rate of patients treated by the shorter injectable based regimen.
| S-EPMC8797248 | biostudies-literature