Stakeholders' perspective on the daily regimen of tuberculosis treatment- A qualitative approach.

INTRODUCTION: In the context of changing over from an intermittent treatment regimen to a daily regimen, it becomes crucial to understand the impact of a daily regimen on the treatment process and outcome. It enables health professionals to strengthen strategies, to enhance the quality of treatment as well as the quality of life of TB patients. The perspective of each stakeholder involved in the process is important in assessing the impact of the daily regimen. OBJECTIVES: To understand patients' and providers' perspectives on the daily regimen of Tuberculosis treatment. METHODOLOGY: A qualitative study was conducted between March 2020 to June 2020, including in-depth interviews with TB patients on treatment and DOT providers, and Key Informant Interview(KII) with TB Health Visitors(TBHV) and family members of TB patients. A thematic-network analysis approach was utilized to get the results. RESULTS: Two sub-themes emerged: (i) Acceptance of the daily regimen of treatment; (ii) operational difficulties of the daily regimen. No injections in the regimen, fewer side effects of drugs as dose depends on weight band, family members can be treatment supporter, awareness about disease and treatment, the drugs are as same as private drugs available, adherence has improved, monthly DBT were found to some of the enablers in the study. The Barriers found in the study were traveling daily to get drugs, loss of daily wages, accompanying patients daily, tracing private patients, pyridoxine is not given free in this regimen, increased workload for treatment providers, etc. CONCLUSION: The study points out that acceptance of the patient to the daily regimen is better as they have lesser side effects. The operational difficulties in the implementation of the daily regimen can be addressed by providing family members as treatment supporters.

Pharmacokinetics of rifampicin, isoniazid & pyrazinamide during daily & intermittent dosing: A preliminary study.

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 µg/ml vs. 5.5 µg/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 µg/ml vs. 10.9 µg/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 µg/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Perception of DOTS providers on changes in tuberculosis case management: Comparison of alternate day and daily treatment regimens using mixed method design in Mandya district.

BACKGROUND: Tuberculosis case management has undergone various changes in recent years. Most of the decisions have been taken based on provider intelligence or perspective. It is essential to know the beneficiary perspective about the changes in RNTCP. DOTS providers are active witnesses for the series of changes and they have first hand experience of effect of these changes on TB patients. Thus it is ideal to learn from DOTS providers, about comparative strengths and limitations of the new strategy and effects of the changes. METHODS: Study design Mixed method using survey and matrix ranking method. STUDY POPULATION: DOTS providers who have supervised at least one patient before the daily regimen and completed at-least intensive phase of one patient in daily regimen. Study was conducted in Mandya district between May-June 2019 involving 25 DOTS providers selected through snowball sampling technique. Data collection was done using proforma and Matrix ranking technique using 10 stones. Thematic analysis, wilcoxon sign rank test were used for analysis. RESULTS: Significant improvement was reported by DOTS providers in new regimen with respect to compliance, treatment response, ease of supervision and patient attitude towards outcome. Related to drug supply system, there was no significant difference. CONCLUSIONS: There was significant improvement in compliance, response, ease of supervision and patient attitude. Significant reduction in side effects in daily regimen compared to alternate day regimen. NPY is helping poor and elderly patients but irregular payment is an issue. Remuneration of DOTS providers was not consistent.

Adverse drug reaction profile of daily regimen antituberculosis treatment.

Objectives: The objective was to estimate the proportion of adverse drug reactions (ADRs) to daily regimen antituberculosis treatment (ATT) among the ADRs received in the ADR monitoring center (AMC) of the institution and to describe its pattern. Materials and Methods: This was a descriptive study conducted in the Department of Pharmacology of a Government Medical College in Central Kerala and the period under study was October 2017-June 2020. The data on ADR were entered into a structured pro forma and data were analyzed using SPSS for Windows Version 16.0 (SPSS Inc., Chicago, USA). Results: Of the 643 ADRs, 98 (15.24%) were suspected to be due to the daily regimen of ATT. The most common organ system affected was hepatobiliary 46 (46.9%) namely hepatitis in 35 and asymptomatic elevated liver enzymes in 11 followed by eye with 26 reports of decreased vision. In 96 (97.95%), the suspected ADR had probable causality and in 2 (2.04%) it was possible. Seventy-seven (78.6%) ADR reports were serious as well as moderate-level 4b in severity and 57 (58.16%) were probably preventable. The mean days of onset of ADR after starting the ATT regimen were 56.40 ± 58.29 days (range 1-180). Decrease in vision with a mean duration of 125.23 ± 55.46 days had the longest latency in onset among all the ADRs. Conclusions: Of all the ADRs reported to AMC 15.24% were due to the daily regimen of ATT. Hepatitis was the most common ADR encountered followed by decrease in vision. The majority of the ADRs were probable in causality, serious, moderate-level 4b in severity, and probably preventable.

Appraisal on patient compliance and factors influencing the daily regimen of anti-tubercular drugs in Mangalore city: A cross-sectional study.

Background: Globally, India is the country with the highest tuberculosis (TB) burden with respect to the number of new cases occurring each year. Annual incident cases of TB in India accounts for more than 25% of total TB morbidity and mortality worldwide. Several factors have been associated with the adherence of TB medication, which can be broadly classified as patient/personal, social, structural and health service. The aims of the present study were to determine the compliance to daily regimen of directly observed treatment, short-course (DOTS) therapy among TB patients registered at the Tuberculosis Unit (TU) of Mangalore and to identify the factors influencing non-compliance for treatment. Methods: A cross sectional study was performed. The study sample was drawn from the TUs, General Hospital, Mangalore, after taking permission from District TB Officer. The names and addresses of TB patients were collected from treatment cards. The TB patients were approached at their homes/DOTS centers/Primary Health Centre's (PHCs) with the help of senior treatment supervisors. Results: It was found that patients positive for human immunodeficiency virus (HIV) were more likely to be non-adherent, which was statistically significant. Amongst the participants, 66 (33%) were diabetic and 28.8% of them were found to be non-adherent. The proportion of non-adherence was 27 times higher in those with poor patient provider relationships. Patients who reported to have side effects of TB medication were 5.23 times more likely to be non-adherent. Conclusions: Advice on routine consultation with the health care facility, adherence to treatment regimen and education about its benefits should be the prime focus of providing health education to all TB patients, both at the individual and community levels.

Once-daily rabeprazole, levofloxacin, clarithromycin-MR, and bismuth for Helicobacter pylori eradication: A randomized study of 7 or 14 days (ONCE study).

OBJECTIVE: Most therapies for Helicobacter pylori eradication utilize multiple drugs given 2-4 times daily. Patient adherence has been an impediment to reliably achieving high success. This study evaluated a once-daily dosing H pylori eradication regimen. METHODS: A prospective randomized pilot study of H pylori eradication compared once-daily treatment regimen containing levofloxacin (750 mg), clarithromycin-MR (1 g), rabeprazole (60 mg), and bismuth subsalicylate (1,048 mg) for a 7 or 14 days. CYP2C19 genotype and antibiotic susceptibility tests were performed. Successful eradication was defined as negative 13C-urea breath test at least 4 weeks after completion of treatment. RESULTS: 100 subjects were randomized (40 men, 60 women with mean age =54 years). The eradication rates were as follows: 94% (47/50; 95%CI 0.87-1.01) and 84% (42/50; 95%CI 0.73-0.95) with 14-day and 7-day therapy (OR 0.34; 95%CI 0.08-1.35, P = 0.06), respectively. Resistance rates were as follows: 13.0% for clarithromycin, 26.0% for fluoroquinolone, 2.9% for dual clarithromycin-fluoroquinolone resistance, and 62.8% for metronidazole. The 14-day regimen provided 100% eradication in patients with levofloxacin susceptible strain irrespective of the presence of clarithromycin resistance. CYP2C19 genotypes had no effect on cure rates. CONCLUSIONS: The once-daily 14-day rabeprazole-, levofloxacin-, clarithromycin-MR-, and bismuth-containing therapy provided high eradication rate suggested that triple therapies with a PPI, bismuth, and clarithromycin-MR or levofloxacin would be highly effective for once-a-day tailored therapy or as empiric therapy for first-line regimen.

Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen.

BACKGROUND: Although the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG. METHODS: We performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin. RESULTS: A total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21-17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26-19.63; P=0.0006). CONCLUSION: Our study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.

Assessment of microbiological status after successful completion of intermittent revised national tuberculosis control programme directly observed treatment, short course regimen for microbiologically confirmed pulmonary tuberculosis cases: While new daily regimen going to be implemented in India.

Purpose: The Revised National Tuberculosis Control Programme (RNTCP) is now introducing daily fixed-dose regimen instead of Directly Observed Treatment, Short Course (DOTS) regimen for treatment of drug-sensitive tuberculosis (TB) in India. It would be beneficial to understand the drawbacks, barriers and advantages of the existing system for better implementation of new policy. Our study was aimed to evaluate the current microbiological status of new microbiologically confirmed pulmonary TB patients who have successfully completed intermittent DOTS regimen within last 2 years and also to find the economic barriers faced by beneficiaries to avail DOTS treatment. Materials and Methods: We included patients who had completed CAT 1 DOTS regimen within the last 2 years. The patients were interviewed. Sputum sample was collected for microscopy and cartridge-based nucleic acid amplification test. Results: All patients were adhered to intermittent DOTS therapy, and sputum conversion rate was 83%. Minor gastrointestinal side effects were experienced by 60% of cases and 87% consumed drugs under supervision. On microbiological examination, 10% of the study population was found to be positive for TB and they all were rifampicin sensitive. Those who had completed treatment within 1 year with no clinical symptoms re-appeared after treatment. Conclusion: Till date, RNTCP does not follow up the patients for any period of time after successful completion of treatment. Through the present study, we could find relapse cases in 10% of the previously treated non-symptomatic patients. These unnoticed relapse cases have potential to spread TB and increase disease burden of country. Thus, we can conclude that RNTCP has to follow up the patients after successful treatment to determine whether they relapse. It is needed for the success of programme and control of the disease in the country.

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India.

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (Cmax), the area under the concentration-time curve from 0-6 h (AUC0-6h) and treatment outcome were determined. Ninety-two percent of patients had an INH Cmax > 3 µg/mL. Seventy-seven percent of patients had a RIF Cmax < 8 µg/mL and 28% of patients had a RIF AUC0-24h < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses.

Rapid assessment of facilitators and barriers related to the acceptance, challenges and community perception of daily regimen for treating tuberculosis in India.

INTRODUCTION: The Revised National Tuberculosis Control Program (RNTCP) is the largest tuberculosis (TB) control program in the world based on Directly Observed Treatment Short-Course (DOTS) strategy. Globally, most countries have been using a daily regimen and in India a shift towards a daily regimen for TB treatment has already begun. The daily strategy is known to improve program coverage along with compliance. Such strategic shifts have both management and operational implications. We undertook a rapid assessment to understand the facilitators and barriers in adopting the daily regimen for TB treatment in three Indian states. METHODS: In-depth interviews were planned across six districts of three purposively selected states of Maharashtra, Bihar and Sikkim, among health system personnel at various levels to identify their perspectives on adoption of a daily regimen for TB. These districts were sampled on the basis of TB notification rates. Thematic analysis of the qualitative data was undertaken. RESULTS: 62 respondents were interviewed from these 6 districts. During the analysis, it was observed that an easily accessible, patient-centred and personalized outreach is an enabling factor for adherence to treatment. Lack of transportation facilities, out-of-pocket expenses and loss of wages for accessing DOTS at institutions are major identified barriers for treatment adherence at individual level. At program level, lack of trained service providers, poor administration of treatment protocols and inadequate supervision by health care providers and program managers are key factors that influence program outcomes. CONCLUSION: A major observation that emerged from the interviews is that the key to achieve a relapse-free cure is ensuring that a patient receives all doses of the prescribed treatment regimen. However, switching to a daily regimen makes adherence difficult and thus new strategies are needed for its implementation at patient and health provider levels. Most stakeholders appreciate the reasons for switching to a daily regimen. The stakeholders recognised the efforts of the Ministry of Health & Family Welfare (MoHFW) in spearheading the program. Strategies like the 99 DOTS call-centre approach may also further ensure treatment adherence.

Olodaterol for the treatment of asthma.

INTRODUCTION: Long-acting ß-agonist (LABA)/inhaled corticosteroid (ICS) combinations are still the mainstay of asthma therapy but there is a pressing need to increase adherence to the prescribed treatment achievable in general by reducing the dose frequency. Consequently, there is considerable interest within the pharmaceutical industry in the discovery of once-daily ß2-agonists (ultra-LABAs) to be used as a part of a combination therapy for treating asthma. AREAS COVERED: The authors review the preclinical and clinical development of olodaterol, a new ultra-LABA characterized by an improved selectivity for ß2-adrenoceptors and a rather high intrinsic efficacy profile, in asthma. The clinical results were generated by 4 Phase 2 trials, which have enrolled 731 asthmatic patients. EXPERT OPINION: The available results indicate that olodaterol is able to induce an effective 24-h bronchodilation and is safe. However, one cannot formulate a solid conclusion on the best dose and/or dose frequency to be used in asthma because trials were not powered to assess the differences between doses and dose frequencies. Apparently, there is no Phase 3 trial planned or ongoing for olodaterol monotherapy in patients with asthma and also no attempt to combine olodaterol with an ICS, which is surprising.

Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation.

Busulfan (Bu) is widely used in conditioning regimens for infants undergoing allogeneic hematopoietic progenitor cell transplantation (HPCT), but the best approach to administer Bu in this population is still unknown. Here, we report a single-center experience of the use of a test dose to guide dose adjustment of intravenous (i.v.) Bu therapy in infants. Between 2004 and 2013, 33 infants younger than 1 year with nonmalignant conditions received allogeneic peripheral blood or cord blood HPCT after a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, antithymocyte globulin, and 2 single daily doses of i.v. Bu. Pharmacokinetic results of a test dose of i.v. Bu (.8 mg/kg) were used to determine the dose of 2 single daily i.v. Bu regimen doses, adjusted to target an area under the curve (AUC) of 4000 µMol*minute per day in a first cohort (n = 12) and 5000 µMol*minute in a second cohort (n = 21). The mean Bu clearance in our infant patients was found to be 3.67 ± 1.03 mL/minute/kg, and the test dose clearance was highly predictive of the regimen dose clearance. The mean AUC achieved after the first single daily regimen dose was 3951 ± 1239 in the AUC 4000 cohort and 4884 ± 766 for the AUC 5000 cohort. No patient in either cohort developed hepatic sinusoidal obstructive syndrome or seizures attributable to Bu. Primary graft failure occurred in 4 patients and secondary graft failure occurred in 3, predominantly in the AUC 4000 cohort (6 of 7). Among the engrafted patients (n = 28), 16 achieved full donor chimerism and 9 patients attained stable mixed chimerism. Overall survival of patients at 6 years after transplantation was 59.5% for the AUC 4000 cohort and 85.4% for the AUC 5000 cohort, with primary graft failure in the first cohort being a major contributor to morbidity. Logistic regression analysis showed that the risk of graft failure increased significantly if cord blood hematopoietic progenitor cells were used or if total Bu exposure was below 4000 µMol*minute per day for 2 days. The difference in clinical outcomes between the 2 cohorts supports the conclusion that targeting a higher Bu AUC of 5000 µMol*minute per day for 2 days improves donor engraftment in infants with nonmalignant conditions undergoing RIC HPCT without increasing toxicity. Measuring i.v. Bu pharmokinetics using a test dose allows timely adjustment of single daily regimen doses and optimization of total Bu exposure, resulting in an effective and safe regimen for these infants.

Comparing the Daily Versus the Intermittent Regimens of the Anti-Tubercular Chemotherapy in the Initial Intensive Phase in Non-HIV, Sputum Positive, Pulmonary Tuberculosis Patients.

BACKGROUND: Tuberculosis (TB) is a major health problem in the universe and India is no longer exempted from this crisis .The emergence of HIV and MDRTB (Multi Drug Resistant Tuberculosis) have further made the situation critical. AIMS: Our aim was to compare the efficacy of the daily and the intermittent doses of the Anti Tubercular Drug (ATD) therapy which is under the Revised National Tuberculosis Control Programme, amongst the sputum positive pulmonary tuberculosis in terms of the sputum conversion rate at the end of the initial phase , the default rate and the adverse drug reactions. METHODS: This was an observational prospective study. MATERIAL: Eighty three patients were selected from the out patient and the inpatient departments of a tertiary medical centre in India. RESULTS: Forty three cases received an intermittent regimen, where the major age group belonged to the under 40 years age group, the default rate to the therapy was 9.3%, the sputum conversion rate was 94.87% and adverse drug reactions were found in 25.58% of the patients. In the daily regimen, there was an equal proportion of the age group of the patients, both above and below 40 yrs, the sputum conversion rate was 94.74%, a default rate was found in 5% cases and adverse reactions were found in 35% of the cases. CONCLUSION: Both the intermittent and the daily regimens showed equal sputum conversion rates and the drug default cases were found more in the intermittent group. However, the adverse reactions were found more in the daily regimen category.

Atriplatrade mark - HIV therapy in one pill.

In July 2006 Atriplatrade mark was approved by the US Food and Drug Administration (FDA), combining the active ingredients of one NNRTI and two NRTIs. Atriplatrade mark is the first "one-pill-daily" regimen licensed for the treatment of HIV-1 infection in patients older than 18 years. H was licensed in Europe in December 2007 Atriplatrade mark contains efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. It therefore combines 3 compounds which have been widely used before and which were recommended for initial therapy due to their potency, tolerability, and safety profile. Efficacy and safety data of efavirenz, tenofovir DF, and emtricitabine are reviewed and compared with other antiretroviral drugs, which are used as initial therapy for treatment-naive patient.