Tuberculosis Treatment Regimens Research Articles

Hepatotoxicity Induced by Anti-Tuberculosis Medications: Exploring Causes, Risk Factors, and Potential Mitigation Strategies

Tuberculosis (TB), a global health concern, remains a leading cause of mortality, with 9 million new cases and 1.7 million deaths reported in 2004. This review delves into a critical facet of TB treatment-antituberculosis drug-induced hepatotoxicity (ATDH). Beyond the direct threat to patients' health, ATDH hampers the efficacy of the prescribed medications. Recognized as a prime contributor to idiosyncratic hepatotoxicity worldwide, anti-TB drugs present a complex interplay of treatment regimens, hepatotoxicity thresholds, patient cohorts, and monitoring protocols.The study comprehensively addresses the incidence, pathophysiology, and clinical dimensions of ATDH, emphasizing the metabolism and toxicity mechanisms of key drugs-isoniazid, rifampicin, and pyrazinamide. Occurring in 2% to 28% of individuals, hepatotoxicity induced by first-line anti-TB drugs can manifest as immediate liver damage, failure, or even necessitate emergency transplantation. Notably, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, and rifapentine fall under this category.In conclusion, ATDH spans a spectrum from asymptomatic enzyme elevations to life-threatening liver failure. Despite widespread usage, the etiology of ATDH remains elusive. The review underscores the importance of investigating drug-related, host genetic, and environmental factors contributing to hepatotoxicity. Emphasizing the need for future research, the article calls for a deeper understanding of the mechanistic underpinnings, exploration of genetic risk factors, and the development of shorter, safer TB treatment regimens to mitigate this significant challenge in global health

The Role of Pyridoxine in the Prevention and Treatment of Neuropathy and Neurotoxicity Associated with Rifampicin-Resistant Tuberculosis Treatment Regimens: A Topic Review

The Role of Pyridoxine in the Prevention and Treatment of Neuropathy and Neurotoxicity Associated with Rifampicin-Resistant Tuberculosis Treatment Regimens: A Topic Review

Clinical profile and outcome in patients with rifampicin-resistant tuberculosis taking shorter multidrug-resistant tuberculosis treatment regimen at a tertiary care hospital in South Gujarat

Background: India remains one of the six countries with an enormous multidrug-resistant tuberculosis (MDR TB) burden. Shorter MDR regimen is more economical/cheaper, shorter and having an improved adherence for Rifampicin resistant (RR)-TB. There were not many studies on this shorter MDR regimen (containing high-dose moxifloxacin) in India, we had carried out this study to find out outcomes and adverse drug reactions (ADRs) of this Shorter MDR regimen. Aims and Objectives: To study the clinical profile, interim and final outcome, and ADRs in RR-TB patients taking shorter MDR regimens. Materials and Methods: Prospective observational longitudinal study which was carried out in the Department of Respiratory Medicine Department, New Civil Hospital, Surat from January 2019 to June 2020. All patients who were diagnosed as RR-TB by cartridge-based nucleic acid amplification were enrolled in the study. Eligible Patients (n = 60) were started on shorter MDR regimen and were followed up. Results: Out of these 60 patients 35 (58.3%) were male and 25 (41.6%) were female. The age group mainly included was between 20 and 40 years. Out of 60 patients, 55 (91.6%) had pulmonary and 5 (8.3%) had extrapulmonary TB. Interim Outcome in the form of culture conversion at the end of 4th, 5th, and 6th month was seen in 21 (45.65%), 37 (80.43%), and 45 (97.83%), respectively. The final outcome among 60 patients were 33 (55%) cured, 12 (20%) treatment completed, 6 (10%) lost to follow-up, 5 (8.33%) regimen changed, 3 (5%) died, and failure in 1 (1.66%). These results were matching with most of the other studies. Conclusion: This study showed successful outcome (cured and treatment completed) in 45 patients (75%) and adverse outcome (died, lost to follow-up, and failure) in 10 patients (16.67%). A shorter MDR regimen is shorter, cheaper, effective in most of the RR-TB patients and is well tolerated with mild side effects.

More treatment options for rifampicin-resistant tuberculosis: the role of economic evaluation in informing uptake

There have been substantial advances in treatment options for multidrug-resistant and rifampicin-resistant tuberculosis. Just a few years ago, a typical patient faced months of painful injections, life-changing adverse effects, and a very small chance of cure. This year, WHO announced forthcoming updates to global guidelines including 6-month and 9-month all-oral regimens for treatment of multidrug-resistant and rifampicin-resistant tuberculosis.1 In the context of these rapidly changing options for treating multidrug-resistant and rifampicin-resistant tuberculosis and persisting high costs of newer drugs such as bedaquiline, countries are facing difficult decisions about when and how to incorporate new drug regimens into national guidelines, and the economic effects of new regimens will be a key consideration in their uptake.

Economic evaluation of shortened, bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis (STREAM stage 2): a within-trial analysis of a randomised controlled trial

The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens. STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631. 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India. At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable. USAID and Janssen Research & Development.

Consensus statement on the use of a four-month treatment regimen for drug susceptible tuberculosis in children (< 10 years of age) with uncomplicated disease

Consensus statement on the use of a four-month treatment regimen for drug susceptible tuberculosis in children (< 10 years of age) with uncomplicated disease

Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies.

There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

Cost-effectiveness of short, oral treatment regimens for rifampicin resistant tuberculosis.

Current options for treating tuberculosis (TB) that is resistant to rifampicin (RR-TB) are few, and regimens are often long and poorly tolerated. Following recent evidence from the TB-PRACTECAL trial countries are considering programmatic uptake of 6-month, all-oral treatment regimens. We used a Markov model to estimate the incremental cost-effectiveness of three regimens containing bedaquiline, pretomanid and linezolid (BPaL) with and without moxifloxacin (BPaLM) or clofazimine (BPaLC) compared with the current mix of long and short standard of care (SOC) regimens to treat RR-TB from the provider perspective in India, Georgia, Philippines, and South Africa. We estimated total costs (2019 USD) and disability-adjusted life years (DALYs) over a 20-year time horizon. Costs and DALYs were discounted at 3% in the base case. Parameter uncertainty was tested with univariate and probabilistic sensitivity analysis. We found that all three regimens would improve health outcomes and reduce costs compared with the current programmatic mix of long and short SOC regimens in all four countries. BPaL was the most cost-saving regimen in all countries, saving $112-$1,173 per person. BPaLM was the preferred regimen at a willingness to pay per DALY of 0.5 GDP per capita in all settings. Our findings indicate BPaL-based regimens are likely to be cost-saving and more effective than the current standard of care in a range of settings. Countries should consider programmatic uptake of BPaL-based regimens.

Estimation of Functional Exercise Capacity in Pulmonary Tuberculosis Survivors

Background: Pulmonary tuberculosis (PTB) is the main apprehension universally. Although treatable, tuberculosis (TB) endures depressingly and disturbs patients’ health-related quality of life (HRQoL) and functioning even after treatment.1 Resources have revealed that multidrug treatments can lead to unwanted adversative drug reactions such as arthralgia, neurological disorders, hepatotoxicity, and allergic reactions. TB affects the respiratory system, that is, airflow patterns, functional exercise capacity, and ultimately the QoL of patients even after the completion of the 4-month rifapentine-moxifloxacin TB treatment regimen and 6- or 9-month rifapentine, isoniazid, pyrazinamide, and ethambutol (RIPE) TB treatment regimen. Throughout the treatment of active PBT, lung function damage is usually restrictive. Materials and methods: A total of 86 PTB survivors were selected for the PTB survivors’ group, who had a history of taking complete treatment for PTB. Each survivor was evaluated for functional exercise capacity with a 12-minute walk test (MWT), 15-step oximetry test, and HRQoL questionnaire. Results: Pulmonary tuberculosis (PTB) causes variation in vitals and also has negative effects on physical functioning. The study results demonstrated that out of 86 total respondents, the majority (97–100%) had better oxygen levels pretest (12-MWT and pulse oximetry) with an average of 17–20 bpm. 47% of individuals were underweight, with posttest oxygen saturation reduced to 91–93% and respiratory rate increased to 26–30 bpm. QoL was also compromised. Conclusion: This present study concluded that PTBs and their treatment do affect the functional exercise capacity of the survivors. The respiratory rate and blood pressure are markedly increased, whereas the oxygen saturation and manual muscle strength are markedly reduced. PTB survivors also suffered from compromised health and QoL, that is, emotional and mental weaknesses.

Applying Psychological and Educational Health Models to Determine the Effect of a Pharmacist-led Cognitive and Behavioral Intervention on Tuberculosis Treatment Outcomes in Plateau State, Nigeria.

Background: The prolonged multi-drug treatment regimen for tuberculosis (TB) can lead to non-adherence and unsuccessful treatment outcomes. Educational and psychological health models can be used to design cognitive and behavioral interventions to improve adherence and treatment outcomes. Objective: To determine the effect of cognitive and behavioral interventions on TB treatment outcomes. Methods: The quasi-experimental study conducted in six TB treatment centers involved reinforced medication education and adherence counseling (MEAC), designed from a structured validated psychometric scale. Data were collected three different times during the intensive and continuation phases of treatment from 463 TB patients (232 in the control and 231 in the intervention group). Baseline demographic and clinical characteristics were compared between the groups. The generalized estimating equation model was used to analyze the repeated measures by determining if treatment success was associated with the cognitive and behavioral interventions and medication adherence. Results: The males made up 290(62.6 %) of the population. The mean age was 36.75±13.9. Most of the TB patients were newly diagnosed 413(89.2%) and HIV negative 315(68%), with secondary level of education 216(46.6%). There was no significant difference in baseline characteristics between the groups. The intervention group was four times more likely to have treatment success (p<0.01; CI=1.5-8.4), compared to the control group. Medication-adherent TB patients were 24 times more likely to have treatment success than patients who did not adhere (p<0.001; 10.8-52.1). TB patients' emotions, attitudes, and perceptions of their medicines were predictors of treatment success (p<0.05; 1.0 - 1.1). Conclusion: The cognitive and behavioral interventions administered to TB patients improved successful treatment outcomes.

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

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). 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. 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). 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.

Are We Moving Towards Development of Universal Drug Regimen for Treatment of Tuberculosis?

Are We Moving Towards Development of Universal Drug Regimen for Treatment of Tuberculosis?

Safety and effectiveness of all-oral and injectable-containing, bedaquiline-based long treatment regimen for pre-XDR tuberculosis in Vietnam.

Background: The World health organization (WHO) recently recommended standardized all-oral shorter regimens for rifampicin resistant Tuberculosis (RR-TB). For highly resistant Tuberculosis patients such as pre-XDR-TB: RR-TB plus additional resistance to fluoroquinolones (FQ), the 6–9-months bedaquiline (bedaquiline)-based regimens or BDQ-based long regimens are recommended. The role of second-line injectable (SLI) drugs in the treatment of drug resistant TB is restricted because of safety concerns. Nevertheless, it is not well-known how all-oral long regimens (BDQ-long) perform compared to SLI-containing long regimens (BDQ/SLI-long) in terms of safety and effectiveness among patients with highly resistant TB. Method: A prospective observational cohort of patients with RR-TB additionally resistant to fluoroquinolones and/or second-line injectable, treated with either BDQ-long or BDQ/SLI-long regimens according to the guidance of the National Tuberculosis Program of Vietnam, enrolled between December 2015 and June 2017. Results: Of 99 patients enrolled, 42 (42%) patients were treated with BDQ-long and 57 (57%) with BDQ/SLI-long. More than 85% of patients were previously exposed to both FQ and SLI. FQ and SLI resistance were confirmed in 28 (67%) and 41 (98%) in the BDQ-long cohort and 48 (84%) and 17 (30%) in the BDQ/SLI-long cohort, respectively. Treatment success was achieved among 29 (69%) and 46 (81%) patients on the BDQ-long and BDQ/SLI-long regimen, respectively (p = 0.2). For both regimens, median time to first smear/culture sputum conversion was 2 months. All patients experienced at least one adverse event (AE) and 85% of them had at least one severe Adverse events. The median time to a first severe adverse event was 2 months. Among patients treated with BDQ-long a higher proportion of patients had three QT-prolonging drugs in the regimen (26.2% versus 7.0%; p = 0.009). The severe prolonged QTcF was observed in 22 (52.4%) and 22 (38.6%) patients on BDQ-long and BDQ/SLI-long, respectively. Overall, 30 (30%) patients had to either temporary or permanently discontinued or more TB drugs due to AEs. Conclusion: Treatment success was similar for both all-oral and SLI-containing BDQ-based long regimens in highly resistant TB patients. Both regimens had a similar high frequency of AEs. For both BDQ-long and BDQ/SLI-long regimens active AEs monitoring is essential.

Cost Effectiveness of a Shorter Moxifloxacin Based Regimen for Treating Drug Sensitive Tuberculosis in India.

Globally efforts are underway to shorten the existing 6-month tuberculosis (TB) treatment regimen for drug-sensitive patients, which would be equally effective and safe. At present, there is a lack of evidence on the cost implications of a shorter 4-month TB regimen in India. This economic modeling study was conducted in the Indian context with a high TB burden. We used a hybrid economic model comprising of a decision tree and Markov analysis. The study estimated the incremental costs, life years (LYs), and quality-adjusted life years (QALYs) gained by the introduction of a Moxifloxacin-based shorter 4-month treatment regimen for pulmonary TB patients. The outcomes are expressed in incremental cost-effectiveness ratios (ICERs) per QALYs gained. The cost per case to be treated under the 4-month regimen was USD 145.94 whereas for the 6-month regimen it was USD 150.39. A shorter 4-month TB regimen was cost-saving with USD 4.62 per LY and USD 5.29 per QALY. One-way sensitivity analysis revealed that the cost of the drugs for the 4-month regimen, hospitalization cost for adverse drug reactions, and human resources incurred for the 6-month regimen had a higher influence on the ICER. The probability sensitivity analysis highlighted that the joint incremental cost and effectiveness using QALY were less costly and more effective for 67% of the iteration values. The cost-effectiveness acceptability curve highlights that the 4-month regimen was dominant to both patients and the National TB Elimination Programme in India as compared to the 6-month regimen at different cost-effectiveness threshold values.

Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents

Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10–fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.

The Usability and Impact of Mobile Health Applications on Tuberculosis treatment regimen: A Systematic Review

ABSTRACT&#x0D; Introduction: Tuberculosis remains the major public health problem worldwide. including in Indonesia. Adherence to the therapeutic regimen is one of the indicators in the TB management. However, drop-out among those undergoing TB therapeutic regimen was found to be high. This study aims to review published articles on the usefulness of mobile health apps on adherence to TB treatment regimens and in healthcare workers.&#x0D; Method: This systematic review applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) guideline. The results was reported in descriptive narrative approach. The following data bases; Scopus, Pubmed, and Proquest were comprehensively searched to find articles from January, 1st 2018 to December 31st 2023. Inclusion was made to English and full-text articles.&#x0D; Results: Fourteen (14) articles were yielded. A total of 2.408 TB sufferers and health workers use the mobile health application. Findings on the impacts of the usability of mobile health application on the adherence of TB’s treatment regimen: TB sufferers mostly use mobile health to access information about TB via SMS (Short Message Service), WhatsApp messenger, voice or telephone calls, A video-observed therapy (VOT), or using a toll-free mobile health modification, namely 99DOTS.&#x0D; Conclusions: Mobile health application tended to benefits people living TB. The findings of the study emphasize the importance of mobile health application on TB management. Mobile health apps increase patient’s motivation to adhere to the recommended regimen as one of the key used the TB management strategies.&#x0D; &#x0D; Keyword: Tuberculosis, Mobile health, Treatment, Adherence, Nursing informatics

Costs Associated with Adverse Drug Reactions Among HIV/TB Patients in Thailand.

PurposeTo assess the direct and indirect costs associated with adverse drug reactions (ADRs) in patients receiving treatment regimens for human immunodeficiency virus (HIV) infection and tuberculosis (TB) in selected Thai hospitals.Patients and MethodsThis was a retrospective study conducted between October 2014 and September 2019 at three public hospitals in Thailand. Data were obtained from a medical database and spontaneous ADR reporting system of each study site. The out-of-pocket health payments and indirect costs were determined via interviewing. All costs were updated to 2021.ResultsA total of 432 eligible patients who experienced ADRs due to HIV and TB treatment, and 93 patients were interviewed to determine direct non-medical and indirect costs. The average direct medical cost for ADR was USD 5.65 for mild cases, USD 156.54 for moderate cases, and USD 1,242.45 for severe cases. For direct non-medical costs, the average cost per episode was USD 27.29 in mild ADR, USD 70.86 in moderate ADR and USD 270.66 in severe ADR. The indirect cost incurred in each mild, moderate and severe ADR was USD 41.86, USD 89.34, and USD 552.60, respectively. The Stevens-Johnson syndrome (SJS) had the highest management costs.ConclusionADRs associated with anti-tuberculosis drugs and antiretroviral drugs seem to have a substantial economic impact from a societal perspective. These findings would be useful for increasing awareness and encouraging early avoidance of ADRs.

Design principles to assemble drug combinations for effective tuberculosis therapy using interpretable pairwise drug response measurements

SummaryA challenge in tuberculosis treatment regimen design is the necessity to combine three or more antibiotics. We narrow the prohibitively large search space by breaking down high-order drug combinations into drug pair units. Using pairwise in vitro measurements, we train machine learning models to predict higher-order combination treatment outcomes in the relapsing BALB/c mouse model. Classifiers perform well and predict many of the >500 possible combinations among 12 antibiotics to be improved over bedaquiline + pretomanid + linezolid, a treatment-shortening regimen compared with the standard of care in mice. We reformulate classifiers as simple rulesets to reveal guiding principles of constructing combination therapies for both preclinical and clinical outcomes. One example ruleset combines a drug pair that is synergistic in a dormancy model with a pair that is potent in a cholesterol-rich growth environment. These rulesets are predictive, intuitive, and practical, thus enabling rational construction of drug combinations.

Adherence to Anti-tubercular Agents in DOTS Center in Western Nepal

INTRODUCTION: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and is one of the major public health problems in developing countries like Nepal. Despite the availability of effective tuberculosis treatment regimens, patients must take a combination of anti-tubercular drugs for at least six months and may endure numerous side effects, making treatment compliance exceedingly difficult to maintain. The primary objective of the study was to assess the adherence rate to anti-tubercular agents and to find the prevalence of adverse drug reactions to the anti-tubercular therapy. MATERIALS AND METHODS: This study was an observational study conducted in the DOTS centers of UCMS-TH, Bhairahawa, and Lumbini Provincial Hospital Butwal. A semi-structured questionnaire was used to collect data from 170 participants to determine the adherence rate to anti-tubercular therapy and the incidence of associated adverse drug reactions. Statistical Package for Social Sciences (SPSS Version 20) program was used to enter and analyze the data. The association between adherence and other variables was established using the Chisquare test. RESULTS: The adherence rate to anti-tubercular therapy was found to be 159 (93.5%). The major reasons for non-adherence include forgetfulness 8 (72.72%) followed by adverse effects 2 (18.18%) and transport difficulty in reaching the health facility 1 (9.1%). The prevalence of adverse drug reactions was 58 (34.12%) (27.1 - 41.2 at 95% Confidence Interval). Adherence was significantly associated with the experience of adverse effects, literacy, marital status, area of residence, and age of the participants. CONCLUSIONS: The adherence rate to anti-tubercular therapy was very high, which can be the primary determinant of tuberculosis treatment success.

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

BackgroundThe 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.MethodsThis 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.DiscussionThis 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 registrationClinicalTrials.gov NCT04485156. Registered on July 24, 2020.