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Directly observed treatment (DOT) has been the standard of care for tuberculosis since the early 1990s, but it is inconvenient for patients and service providers. Video-observed therapy (VOT) has been conditionally recommended by WHO as an alternative to DOT. We tested whether levels of treatment observation were improved with VOT. We did a multicentre, analyst-blinded, randomised controlled superiority trial in 22 clinics in England (UK). Eligible participants were patients aged at least 16 years with active pulmonary or non-pulmonary tuberculosis who were eligible for DOT according to local guidance. Exclusion criteria included patients who did not have access to charging a smartphone. We randomly assigned participants to either VOT (daily remote observation using a smartphone app) or DOT (observations done three to five times per week in the home, community, or clinic settings). Randomisation was done by the SealedEnvelope service using minimisation. DOT involved treatment observation by a health-care or lay worker, with any remaining daily doses self-administered. VOT was provided by a centralised service in London. Patients were trained to record and send videos of every dose ingested 7 days per week using a smartphone app. Trained treatment observers viewed these videos through a password-protected website. Patients were also encouraged to report adverse drug events on the videos. Smartphones and data plans were provided free of charge by study investigators. DOT or VOT observation records were completed by observers until treatment or study end. The primary outcome was completion of 80% or more scheduled treatment observations over the first 2 months following enrolment. Intention-to-treat (ITT) and restricted (including only patients completing at least 1 week of observation on allocated arm) analyses were done. Superiority was determined by a 15% difference in the proportion of patients with the primary outcome (60% vs 75%). This trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN26184967. Between Sept 1, 2014, and Oct 1, 2016, we randomly assigned 226 patients; 112 to VOT and 114 to DOT. Overall, 131 (58%) patients had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled observations successfully completed during the first 2 months compared with 35 (31%) of 114 on DOT (adjusted odds ratio [OR] 5·48, 95% CI 3·10–9·68; p<0·0001). In the restricted analysis, 78 (77%) of 101 patients on VOT achieved the primary outcome compared with 35 (63%) of 56 on DOT (adjusted OR 2·52; 95% CI 1·17–5·54; p=0·017). Stomach pain, nausea, and vomiting were the most common adverse events reported (in 16 [14%] of 112 on VOT and nine [8%] of 114 on DOT). VOT was a more effective approach to observation of tuberculosis treatment than DOT. VOT is likely to be preferable to DOT for many patients across a broad range of settings, providing a more acceptable, effective, and cheaper option for supervision of daily and multiple daily doses than DOT. National Institute for Health Research.

Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment. We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course. In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs. ClinicalTrials.gov NCT01960257.

Scaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization's (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa. The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness-implementation randomized trial comparing 3 optimized strategies for delivering 3HP-facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid-to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP (≥11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes. 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion. ClinicalTrials.gov NCT03934931.

The World Health Organization recommends direct observation of treatment (DOT) to support patients with tuberculosis (TB) and to ensure treatment completion. As per national programme guidelines in India, a DOT provider can be anyone who is acceptable and accessible to the patient and accountable to the health system, except a family member. This poses challenges among children with TB who may be more comfortable receiving medicines from their parents or family members than from unfamiliar DOT providers. We conducted a non-inferiority trial to assess the effect of family DOT on treatment success rates among children with newly diagnosed TB registered for treatment during June-September 2012. We randomly assigned all districts (n = 30) in Gujarat to the intervention (n = 15) or usual-practice group (n = 15). Adult family members in the intervention districts were given the choice to become their child's DOT provider. DOT was provided by a non-family member in the usual-practice districts. Using routinely collected clinic-based TB treatment cards, we compared treatment success rates (cured and treatment completed) between the two groups and the non-inferiority limit was kept at 5%. Of 624 children with newly diagnosed TB, 359 (58%) were from intervention districts and 265 (42%) were from usual-practice districts. The two groups were similar with respect to baseline characteristics including age, sex, type of TB, and initial body weight. The treatment success rates were 344 (95.8%) and 247 (93.2%) (p = 0.11) among the intervention and usual-practice groups respectively. DOT provided by a family member is not inferior to DOT provided by a non-family member among new TB cases in children and can attain international targets for treatment success. Clinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2015/09/006229.

Background Tuberculosis (TB) now ranks alongside HIV as the leading infectious disease cause of death worldwide and incurs a global economic burden of over $12 billion annually. Directly observed therapy (DOT) recommends that TB patients complete the course of treatment under direct observation of a treatment supporter who is trained and overseen by health services to ensure that patients take their drugs as scheduled. Though the current WHO End TB Strategy does not mention DOT, only “supportive treatment supervision by treatment partners”, many TB programs still use it despite the fact that the has not been demonstrated to be statistically significantly superior to self-administered treatment in ensuring treatment success or cure. Discussion DOT is designed to promote proper adherence to the full course of drug therapy in order to improve patient outcomes and prevent the development of drug resistance. Yet over 8 billion dollars is spent on TB treatment each year and thousands undergo DOT for all or part of their course of treatment, despite the absence of rigorous evidence supporting the superior effectiveness of DOT over self-administration for achieving drug susceptible TB (DS-TB) cure. Moreover, the DOT component burdens patients with financial and opportunity costs, and the potential for intensified stigma. To rigorously evaluate the effectiveness of DOT and identify the essential contributors to both successful treatment and minimized patient burden, we call for a pragmatic experimental trial conducted in real-world program settings, the gold standard for evidence-based health policy decisions. It is time to invest in the rigorous evaluation of DOT and reevaluate the DOT requirement for TB treatment worldwide. Summary Rigorously evaluating the choice of treatment supporter, the frequency of health care worker contact and the development of new educational materials in a real-world setting would build the evidence base to inform the optimal design of TB treatment protocol. Implementing a more patient-centered approach may be a wise reallocation of resources to raise TB cure rates, prevent relapse, and minimize the emergence of drug resistance. Maintaining the status quo in the absence of rigorous supportive evidence may diminish the effectiveness of TB control policies in the long run.

Latent tuberculosis infection (LTBI) treatment in persons at increased risk of disease progression is a key strategy with the strong potential to increase rate of tuberculosis (TB) decline in the United States. However, LTBI treatment in homeless persons, a population at high-risk of active TB disease, is usually associated with poor adherence. We describe the impact of using directly observed treatment (DOT) versus self-administered treatments (SAT) as an adherence-improving intervention to administer four months of daily rifampin regimen for LTBI treatment among homeless adults in Atlanta. Retrospective analysis of clinical care data on 274 homeless persons who initiated daily rifampin treatment for LTBI treatment at a county health department between January 2014 and December 2016 was performed. To reduce bias from non-random assignment of treatment, an inverse probability of treatment weighted (IPTW) logistic regression model was used to assess the effect of treatment type on treatment completion. Subgroup analyses were performed to assess heterogeneity of treatment effect on LTBI completion. Of 274 LTBI treatment initiators, 177 (65%) completed treatment [DOT 118/181 (65%), SAT 59/93 (63%)]. In the fully adjusted and weighted analysis, the odds of completing LTBI treatment on DOT was 40% higher than the odds of completing treatment by SAT [adjusted odds ratio (95% CI), aOR: 1.40 (1.07, 1.82), p = 0.014]. The unstable nature of homeless persons' lifestyle makes LTBI treatment difficult for many reasons. Our study lends support to the use of DOT to improve LTBI treatment completion among subgroups of homeless persons on treatment with daily rifampin.

Background. The duration of treatment of gastrointestinal tuberculosis continues to be a matter of debate. The World Health Organization advocates intermittent directly observed short-course therapy (DOTs), but there is a lack of data of its efficacy in abdominal tuberculosis. We therefore conducted a multicenter randomized controlled trial to compare 6 months and 9 months of antituberculosis therapy using DOTs. Methods. One hundred ninety-seven patients with abdominal tuberculosis (gastrointestinal, 154; peritoneal, 40; mixed, 3) were randomized to receive 6 months (n = 104) or 9 months (n = 93) of antituberculosis therapy using intermittent directly observed therapy. Patients were followed up 1 year after completion of treatment to assess recurrence. Patients were evaluated for primary endpoint (complete clinical response, partial response, and no response) and secondary endpoint (recurrence of the disease at the end of 1 year of follow-up). Results. Baseline characteristics were similar between the 2 randomized groups. There was no difference between the 6-month group and 9-month group in the complete clinical response rate on per-protocol analysis (91.5% vs 90.8%; P = .88) or intent-to-treat analysis (75% vs 75.8%; P = .89). Only 1 patient in the 9-month group and no patients in the 6-month group had recurrence of disease. Side effects occurred in 21 (21.3%) and 16 (18.2%) patients in the 6-month and 9-month groups, respectively. Conclusions. There was no difference in efficacy of antituberculosis therapy delivered for either 6 months or 9 months in either gastrointestinal or peritoneal tuberculosis, confirming the efficacy of intermittent directly observed therapy. Clinical Trials Registration. NCT01124929.

This study determined whether motivational interviewing-based cognitive behavioral therapy (MI-CBT) adherence counseling combined with modified directly observed therapy (MI-CBT/mDOT) is more effective than MI-CBT counseling alone or standard care (SC) in increasing adherence over time. A three-armed randomized controlled 48-week trial with continuous electronic drug monitored adherence was conducted by randomly assigning 204 HIV-positive participants to either 10 sessions of MI-CBT counseling with mDOT for 24 weeks, 10 sessions of MI-CBT counseling alone, or SC. Poisson mixed effects regression models revealed significant interaction effects of intervention over time on non-adherence defined as percent of doses not-taken (IRR = 1.011, CI = 1.000–1.018) and percent of doses not-taken on time (IRR = 1.006, CI = 1.001–1.011) in the 30 days preceding each assessment. There were no significant differences between groups, but trends were observed for the MI-CBT/mDOT group to have greater 12 week on-time and worse 48 week adherence than the SC group. Findings of modest to null impact on adherence despite intensive interventions highlights the need for more effective interventions to maintain high adherence over time.

Background While investment in the development of Tuberculosis (TB) treatment strategies is essential, it cannot be assumed that the strategies are affordable for TB patients living in countries with high economic constraints. This study aimed to determine the economic consequences of directly observed therapy for TB patients. Methods A cross-sectional cost-of-illness analysis was conducted between September to November 2015 among 576 randomly selected adult TB patients who were on directly observed treatment in 27 public health facilities in Addis Ababa, Ethiopia. Data were collected using interviewer-administered questionnaire adapted from the Tool to Estimate Patients’ Costs. Mean and median costs, reduction of productivity, and household expenditure of TB patients were calculated and ways of coping costs captured. Eta (η), Odds ratio and p values were used to measure association between variables. Results Of the total 576 TB patients enrolled, 43 % were smear-positive pulmonary TB (PTB), 17 % smear-negative PTB, 37 % Extra-PTB and 3 % multi-drug resistant TB cases. Direct (Out-of-Pocket) mean and median costs of TB illness to patients were $123.0 (SD = 58.8) and $125.78 ( R  = 338.12), respectively, and indirect (loss income) mean and median costs were $54.26 (SD = 43.5) and $44.61 ( R  = 215.6), respectively. Mean and median total cost of TB illness to patient were $177.3 (SD = 78.7) and $177.1 ( R  = 461.8), respectively. The total cost had significant association with patient’s household income, residence, need for additional food, and primary income ( P <0.05). Direct costs were catastrophic for 63 % of TB patients, regardless of significant difference between gender ( P  = 0.92) and type of TB cases ( P  = 0.37). TB patients mean productivity and income reduced by 37 and 10 %, respectively, compared with pre-treatment level, while mean household expenditure increased by 33 % and working hours reduced by 78 % due to TB illness. Income quartile categories were directly correlated with catastrophic costs (η = 0.684). Conclusion Despite the availability of free-of-charge anti-TB drugs, TB patients were suffering from out-of-pocket payments with catastrophic consequences, which in turn were hampering the efforts to end TB. TB patients in resource-limited countries deserve integrated patient-centered care with comprehensive health insurance coverage, financial incentives, and nutrition support to reduce catastrophic costs and retain them in care. Such countries should induce home-based directly observed therapy programs to reduce costs due to attending health facilities, intensify home treatment of critically-ill patients with impaired mobility, and reduce the spread of TB due to patients traveling to seek care.