Treatment outcomes of standardized injectable shorter regimen for multi-drugs resistant tuberculosis in Ethiopia: a retrospective cohort study.

BACKGROUND: The injectable shorter multi-drug resistant tuberculosis (MDR-TB) regimen, has been reported to be less costly and more effective in the treatment of MDR-TB compared to the longer regimen. Ethiopia introduced the injectable shorter regimen (SR) in April 2018 following official recommendation by the World Health Organization (WHO) in 2016. While the WHO recommendation was based on evidence coming from extensive programmatic studies in some Asian and African countries, there is paucity of information on patient outcomes in the Ethiopian context. Thus, we aimed to assess the treatment outcomes and identify factors associated with the outcomes of MDR-TB patients on injectable SR. METHODS: A multi-center facility-based retrospective cohort study was conducted in Ethiopia on 245 MDR-TB patients who were treated between April 2018 and March 2020. Data were collected from patients' medical records and analyzed using SPSS version 25. Descriptive statistics was used to summarize the results while inferential analysis was employed to investigate predictors of treatment outcomes and survival status. RESULTS: A total of 245 patients were included in the study, with 129 (52.7%) of them being female. Median age of the patients was 27 (IQR: 21-33). The overall treatment success rate was 87.8%, with 156 (63.7%) cured and 59 (24.1%) patients who completed treatment. The unfavorable outcomes accounted for 12.2%, with 16 (6.5%) treatment failure, 8 (3.3%) death and 6 (2.4%) lost to follow up. Majority of the unfavorable outcomes occurred during the early phase of therapy, with median time to event of 1.8 months (95% CI: 0.99-2.69). The use of khat (a green leafy shrub abused for its stimulant like effect) and being diagnosed with MDR-TB than rifampicin resistant only, were identified as independent factors associated with unfavorable outcomes. CONCLUSION: The injectable SR for MDR-TB was found to have positive treatment outcomes in the context of programmatic management in Ethiopia.

Magnitude and Impacts of Adverse Events of Injectable Containing Shorter Regimen in Programmatic Management of Multi-Drug Resistant Tuberculosis in Ethiopia: A Retrospective Cohort Study.

Background: Since its launch as a standardized treatment for multidrug-resistant tuberculosis (MDR-TB) in Ethiopia in April 2018, the safety profile of the shorter injectable regimen under a programmatic setting has not been well studied. Thus, this study aimed to assess the status of adverse events in patients treated with a shorter injectable regimen in Ethiopia. Methods: This is a retrospective cohort study. Data were collected using a structured data abstraction form and analyzed using SPSS, version 25, both descriptively and analytically. Logistic regression was conducted to assess predictors, and Kaplan-Meier analysis was used to examine the time to AEs and survival experiences. Results: Of 256 patients, 245 (95.7%) were eligible for the study. Of 245, 107 (43.7%) patients experienced at least one AE. In total, 276 AE cases were observed out of which the most common were nausea/vomiting (20.3%), dyspepsia (18.1%), and ototoxicity (11.6%). Of 276 AEs, approximately 49 (17.8%) were serious. AEs led to drug discontinuation, dose modification, and regimen change in 29 (27%), 15 (14%) and 10 (9.3%) patients, respectively. Only 19.2% of 276 the overall AEs and 22.6% of 62 AE of special interest (AESI) were reported to the National Pharmacovigilance Center. Conclusion: Although the observed extent of AEs associated with the shorter regimen (SR) seemed to be moderate, it significantly influenced the treatment schemes and patient conditions. Reporting of AEs was low, irrespective of their severity and AESI. Therefore, strengthening the implementation of active drug safety monitoring and management is required.

Cost of digital technologies and family-observed DOT for a shorter MDR-TB regimen: a modelling study in Ethiopia, India and Uganda.

BACKGROUND: In 2017, the WHO recommended the use of digital technologies, such as medication monitors and video observed treatment (VOT), for directly observed treatment (DOT) of drug-susceptible TB. The WHO's 2020 guidelines extended these recommendations to multidrug-resistant tuberculosis (MDR-TB), based on low evidence. The impact of COVID on health systems and patients underscored the need to use digital technologies in the management of MDR-TB. METHODS: A decision-tree model was developed to explore the costs of several potential DOT alternatives: VOT, 99DOTS (Directly-observed Treatment, Short-course) and family-observed DOT. Assuming a 9-month, all-oral regimen (as evaluated within the STREAM trial), we constructed base-case cost models for the standard-of-care DOTs in Ethiopia, India, and Uganda, as well as for the three alternative DOT approaches. The models were populated with STREAM Stage 2 clinical trial outcome and cost data, supplemented with market prices data for the digital DOT strategies. Sensitivity analyses were conducted on key parameters. RESULTS: Modelling suggested that the standard-of-care DOT approach is the most expensive DOT strategy from a societal perspective in all three countries evaluated (Ethiopia, India, Uganda), with considerable direct- and indirect-costs incurred by patients. The second most expensive DOT approach is VOT, with high health-system costs, largely caused by up-front technology expenditure. Each of VOT, 99DOTS and family-observed DOT would reduce by more than 90% patients' direct and indirect costs compared to standard of care DOT. Results were robust to the sensitivity analyses. CONCLUSIONS: While data on the costs and efficacy of alternative DOT approaches in the context of shorter MDR-TB treatment is limited, our modelling suggests alternative DOT approaches can significantly reduce patient costs in all three countries. Health system costs are higher for VOT and lower for 99DOTS and family-observed therapy when compared to standard of care DOT, as low smartphone penetration and internet availability requires the VOT health system to fund the cost of making them available to patients.

Prospective study on outcome of MDR-TB using the shorter regimen during COVID-19 pandemic.

Background: According to Indian TB report 2020, 66,225 MDR/RR-TB cases were detected in India, 56,569 (85%) were put on treatment, and 40,397 (75%) were initiated on shorter drug regimens at the time of diagnosis. In the absence of an effective vaccine, there is an urgent need for new treatment regimens, drugs, and diagnostics to slow the evolution of drug resistance and limit transmission of resistant variants, as well as to ameliorate the treatment outcome of patients infected with MDR/XDR M. tuberculosis strains. Aim: To evaluate the efficacy of a shorter drug regimen in MDR-PTB and estimate the adverse effects of drugs used in the regimen. Methods: This is an institution-based prospective study which included 135 confirmed MDR-PTB patients. Patients with extra-pulmonary MDR-TB and use of SLI for more than one month were excluded. Results: The success rate using a shorter regimen was 65.2% which is respectable, given the COVID-19 pandemic considered during the study period. Minor adverse events such as nausea (39.3%) and vomiting (34.8%) were reported. Rare adverse effects such as hearing loss (8.9%) and hypothyroidism (0.2%) were also seen in the study population. Conclusion: Overall treatment success was similar when compared to other studies done previously. A shorter drug regimen was associated with minor adverse effects such as gastrointestinal adverse effects such as vomiting and hearing loss observed in elderly patients. Baseline unknown drug resistance and lower BMI were associated with unsuccessful outcomes. Measures should be taken to improve nutrition. Our results argue the need for improving baseline DST at peripheral areas in order to effectively evaluate resistance to other drugs, especially in settings with high levels of first and second-line drug resistance.

Update of drug-resistant tuberculosis treatment guidelines: A turning point.

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Effectiveness and safety of bedaquiline-based, modified all-oral 9-11-month treatment regimen for rifampicin-resistant tuberculosis in Vietnam.

OBJECTIVES: World Health Organization recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR). METHODS: Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid [LZD], clofazimine, and/or pyrazinamide) for patients with RR-TB without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021. RESULTS: A total of 108 patients were enrolled in this study. Overall, 63 of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, six (6%) were lost-to-follow-up, one (1%) died, and four (4%) had treatment failure, including three with permanent regimen change owing to adverse events (AE) and one with culture reversion. Of 108, 32 (30%) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening, or death). The median time to AE was 3 months (IQR: 2-5). A total of 26 AEs led to regimen adaptation: either dose reduction (N = 1), drug temporary interruption (N = 19), or drug permanent discontinuation (N = 6, 4 attributed to LZD). CONCLUSION: The high treatment success of 5-drug mSTR might replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using LZD throughout.

Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis.

Background: The drug regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) has lower potency, is more costly, and has a greater risk of adverse effects than first-line anti-TB drugs. We aimed to compare the treatment outcomes of patients using standard shorter regimen (STR regimen) versus bedaquiline (BDQ)-containing individual regimen in a high TB-burden setting. Methods: This was a retrospective cohort study using secondary data from the medical records in the hospital. The study population were patients with MDR-TB who started treatment in 2016-2018. Treatment outcomes were classified as successful (cured/completed treatment) or unsuccessful (failure/death/loss to follow-up/not evaluated). Categorical data were presented as frequencies and percentage, whereas continuous data were presented as mean± standard deviations. Risk ratio (RR) was obtained by using the Chi-square statistical test with 95% confidence interval (CI) and P < 0.05 set as a significant result. Results: We included 99 patients out of 444 registered patients in 2016-2018. The overall success proportion was 41.4%. Success was more likely in patients who received BDQ regimen than those receiving STR regimen (52.9% vs. 35.4%, RR: 1.496, 95% CI: 0.948-2.362). Factors that influenced the treatment outcomes were smear status and sputum culture status. Conclusions: The success rate of the STR regimen and the BDQ regimen in this study is still below the national and global figures due to the high rate of lost to follow-up. The success was higher in the BDQ regimen, although not statistically significant. Further research is needed on adverse effects, quality of life, and costs during treatment.

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial.

BACKGROUND: The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. METHODS: This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. DISCUSSION: This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. TRIAL REGISTRATION: ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

'Personalizing' shorter regimens: Need of the hour.

INTRODUCTION: The launch of injectable shorter regimens under Programmatic Management of Drug Resistant Tuberculosis (PMDT) guidelines 2017 under Revised National Tuberculosis Control Program (RNTCP) was a welcome step as it decreased the duration of treatment significantly in Drug Resistant Tuberculosis (DRTB) patients. The objective of the present study was to evaluate the treatment outcomes of patients started on injectable shorter regimens from March 2018 to May, 2019. METHODS: Retrospective study which scrutinized medical records of 85 patients started on injectable shorter regimen was conducted. Necessary information on possible patient and disease related predicting factors like age, gender, weight, HIV status, presence of diabetes mellitus (DM), anemia, gap between diagnosis and initiation of treatment, duration of intensive phase (IP) and time of sputum conversion was retrieved, and analyzed for possible association with treatment outcomes. RESULTS: 56.5% had successful treatment outcomes. Age, gender, BMI, diabetic/anemic status and gap between diagnosis and initiation of treatment had no statistically significant relationship with the final outcomes. Duration of IP, sputum conversion and time of outcome during the course of illness emerged as significant factors in successful outcomes. CONCLUSION: The injectable shorter regimens were suitable for a variety of population irrespective of demographic disparities. Patients need to be followed closely as microbiological parameters serve as early indicators of unsuccessful outcomes. These regimens can serve as an alternate choice in patients not tolerating the all oral shorter Bedaquiline containing shorter regimen. Similar such options with combinations of different drugs for individualizing treatment regimens is the need of the hour.

The role of C-Reactive protein as an inflammatory marker to predict prolonged QTc interval in rifampicin-resistant tuberculosis patients: A case-control study.

BACKGROUND: long-term use of anti-tuberculosis drugs (ATD) increases the risk of QTc prolongation, while C-reactive protein (CRP) can be used as an inflammatory marker of Mycobacterium tuberculosis infection.Objective: correlation of CRP on the QTc interval in Rifampicin-resistant tuberculosis (RR-TB) patients with the short regimen. METHODS: An observational study was conducted in Rifampicin-resistant tuberculosis (RR-TB) patients from 2 groups, patients on intensive phase and patients on continuation phase. CRP levels were measured from blood samples and measured automatically using the immunoturbidimetric assay. QTc interval was calculated using electrocardiography. Levels of CRP levels and QTc interval between the 2 groups were analyzed. The statistical analysis used includes the independent t-test, Mann Whitney test, and Rank Spearman test with p = 0.05. RESULTS: Forty-five eligible RR-TB patients were included in this study. CRP levels and QTc intervals between 2 groups (intensive and continuation phase) showed significant difference with p < 0.001 but found no significant correlation of CRP levels and QTc interval in both intensive and continuation phase with p = 0.226 and 0.805, respectively. A higher level of CRP strongly indicated the inflammation caused by RR-TB infection at the early phase of the disease, but not correlated with QTc interval in RR-TB patients. CONCLUSION: Levels of CRP and QTc interval do not correlate in RR-TB patients and can not be used to be the marker of QTc prolongation in RR-TB Patients.

The paradigm shift in the approach to management of latent tuberculosis infection in high tuberculosis burden countries.

Introduction: Addressing the reservoir of Latent Tuberculosis Infection (LTBI) is critical to TB elimination because if left untreated LTBI can progress to active TB disease. This additional burden can prevent achieving the global targets of TB elimination. Management of LTBI has been a low priority target for National TB Elimination Programs (NTEP) due to various challenges in the field settings.Areas covered: This article reviews the most recent advances in the field of LTBI management including newer diagnostics, treatments, vaccines, programmatic challenges, and gaps and suggests a way forward that can be adopted by NTEPs for LTBI. We searched the electronic databases of PubMed, Scopus, and Web of Science for studies published between 2010 to 2020 using MeSH terms: Latent TB Diagnosis, TB preventive therapy, Vaccines, LTBI, and HIV/ COVID.Expert opinion: NTEPs of developing countries should offer a better, point-of-care diagnostic, and effective treatment for LTBI to reduce the number of new TB cases arising from people infected with M.tb. Awareness about LTBI should be increased among the health system staff and the public. More funding is needed to advance research as well as implement the newer findings in the NTEP to achieve the End TB targets by 2035.

Limited Scope of Shorter Drug Regimen for MDR TB Caused by High Resistance to Fluoroquinolone.

Resistance to second-line tuberculosis drugs for patients with multidrug-resistant tuberculosis has emerged globally and is a potential risk factor for unfavorable outcomes of shorter duration drug regimens. We assessed the proportion of patients eligible for a shorter drug regimen in Uttar Pradesh, India, which had the highest rate of multidrug-resistant tuberculosis in India.

Extrapulmonary drug-resistant tuberculosis at a drug-resistant tuberculosis center, Mumbai: Our experience - Hope in the midst of despair!

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a global problem with only 52% reported cure rate. Extrapulmonary (EP) DR-TB poses a formidable diagnostic, therapeutic challenge. We aimed to study their clinical profile and treatment outcomes under the programmatic setting. MATERIALS AND METHODS: This retrospective observational study included the database of consecutive EPDR-TB cases enrolled at the DR-TB center from 2012 to 2014. The demographic, clinical details, drug susceptibility tests (DSTs), follow-up, therapy, adverse events (AEs), and outcome were reviewed. Statistical analysis was done using percentages and mean. RESULTS: Of total 1743 DR-TB patients, 76 (4.4%) EPDR-TB cases were included. These consisted of 53 (69.7%) adults and 23 (30.3%) children, with female preponderance. The mean age in adults and children was 27.96 (9.63) and 12.56 (3.83), respectively. EP sites involved were lymph nodes in 39 (51.3%), spine in 15 (19.7%), other bones in 6 (7.9%), pleural effusion in 9 (11.9%), central nervous system in 2 (2.6%), and disseminated EP disease in 5 (6.6%). Forty-one (53.9%) had multi-DR-TB (MDR-TB), 29 (38.2%) MDR-TB with fluoroquinolone resistance {preextensively DR-TB (Pre-XDR-TB (FQ)), 1 (1.3%) MDR-TB with aminoglycoside resistance (Pre-XDR-TB (AM)), and 5 (6.6%) extensively DR-TB (XDR-TB) on DST. Thirteen (17.11%) had comorbidities. None had HIV. Two (2.63%) had DM. Patients were treated as per the revised TB control program - programmatic management of DR-TB guidelines. Duration of intensive (IP) was 6.55 (1.22) months. Ten (13.2%) received shorter regimens, wherein therapy was stopped at 12-18 months due to severe adverse drug reactions and treatment response. Sixty-two (81.6%) completed treatment, 8 (10.5%) defaulted, 3 (4%) died, 2 (2.6%) failed, and 1 (1.3%) was transferred out. Two-third of patients reported AE. CONCLUSION: The prevalence of EP cases in DR-TB was 4.4%. Treatment completion rate was very high (81.6%). Shorter regimens were efficacious.

Delamanid, linezolid, levofloxacin, and pyrazinamide for the treatment of patients with fluoroquinolone-sensitive multidrug-resistant tuberculosis (Treatment Shortening of MDR-TB Using Existing and New Drugs, MDR-END): study protocol for a phase II/III, multicenter, randomized, open-label clinical trial.

BACKGROUND: Treatment success rates of multidrug-resistant tuberculosis (MDR-TB) remain unsatisfactory, and long-term use of second-line anti-TB drugs is accompanied by the frequent occurrence of adverse events, low treatment compliance, and high costs. The development of new efficient regimens with shorter treatment durations for MDR-TB will solve these issues and improve treatment outcomes. METHODS: This study is a phase II/III, multicenter, randomized, open-label clinical trial of non-inferiority design comparing a new regimen to the World Health Organization-endorsed conventional regimen for fluoroquinolone-sensitive MDR-TB. The control arm uses a conventional treatment regimen with second-line drugs including injectables for 20-24 months. The investigational arm uses a new shorter regimen including delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months depending on time to sputum culture conversion. The primary outcome is the treatment success rate at 24 months after treatment initiation. Secondary outcomes include time to sputum culture conversion on liquid and solid media, proportions of sputum culture conversion on liquid media after 2 and 6 months of treatment, treatment success rate according to pyrazinamide resistance, and occurrence of adverse events grade 3 and above as evaluated by the Common Terminology Criteria for Adverse Events. Based on an α = 0.025 level of significance (one-sided test), a power of 80%, and a < 10% difference in treatment success rate between the control and investigational arms (80% vs. 70%) when the anticipated actual success rate in the treatment group is assumed to be 90%, the number of participants needed per arm to show non-inferiority of the investigational regimen was calculated as 48. Additionally, assuming the proportion of fluoroquinolone-susceptible MDR-TB among participants as 50%, and 5% loss to follow-up, the number of participants is calculated as N/( 0.50 × 0.95), resulting in 102 persons per group (204 in total). DISCUSSION: This trial will reveal the effectiveness and safety of a new shorter regimen comprising four oral drugs, including delamanid, linezolid, levofloxacin, and pyrazinamide, for the treatment of fluoroquinolone-sensitive MDR-TB. Results from this trial will provide evidence for adopting a shorter and more convenient treatment regimen for MDR-TB. TRIAL REGISTRATION: ClincalTrials.gov, NCT02619994 . Registered on 2 December 2015.

Applicability of the shorter 'Bangladesh regimen' in high multidrug-resistant tuberculosis settings.

In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as the 'Bangladesh regimen') proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. However, recent evidence from Europe and Latin America identified prevalences of resistance to the first-line drugs in this regimen (ethambutol and pyrazinamide) exceeding 60%, and of prothionamide exceeding 50%. Furthermore, the proportions of resistance to the two most important pillars of the regimen - quinolones and kanamycin - were higher than 40%. Overall, only 14 out of 348 adult patients (4.0%) were susceptible to all of the drugs composing the regimen, and were therefore potentially suitable for the 'shorter regimen'. A shorter, cheaper, and well-tolerated MDR-TB regimen is likely to impact the number of patients treated and improve adherence if prescribed to the right patients through the systematic use of rapid MTBDRsl testing.