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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.

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.

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. Directly administered antiretroviral therapy (DAART) is one approach to improve treatment adherence among human immunodeficiency virus (HIV)—infected drug users. Methods. In this randomized, controlled trial (ClinicalTrials.gov identifier, NCT00367172), the biological outcomes of a 6-month community intervention of DAART were compared with those of self-administered therapy among HIV-infected drug users. Patients randomized to receive DAART received supervised therapy 5 days per week from workers in a mobile health care van. The primary outcome, using an intention-to-treat approach, was the proportion of patients achieving either a reduction in HIV-1 RNA level of ⩾1.0 log10 copies/mL or an HIV-1 RNA level ⩽400 copies/mL at 6 months. Secondary outcomes included the mean change from baseline in HIV-1 RNA level and CD4+ T lymphocyte count. Results. of the 141 patients who met the entry criteria, 88 were randomized to receive DAART, and 53 were randomized to receive self-administered therapy; 74 (84%) of 88 of the patients randomized to receive DAART accepted the intervention. of the 74 patients who initiated DAART, 51 (69%) completed the full 6-month intervention. At the end of 6 months, a significantly greater proportion of the DAART group achieved the primary outcome (70.5% vs. 54.7; P = .02). Additionally, compared with patients receiving self-administered therapy, patients receiving DAART demonstrated a significantly greater mean reduction in HIV-1 RNA level (-1.16 log10 copies/mL vs. -0.29 log10 copies/mL; P = .03) and mean increase in CD4+ T lymphocyte count (+58.8 cells/μL vs. -24.0 cells/μL; P = .002). Conclusions. This randomized, controlled trial was, to our knowledge, the first to demonstrate the effectiveness of DAART at improving 6-month virologic outcomes among drug users. These results suggest that DAART should be more widely available in HIV treatment programs that target drug users who have poor adherence to treatment.

ObjectivesSuboptimal medication adherence for infectious diseases such as tuberculosis (TB) results in poor clinical outcomes and ongoing infectivity. Directly observed therapy (DOT) is now standard of care for TB treatment monitoring but has a number of limitations. We aimed to develop and evaluate a smartphone-based system to facilitate remotely observed therapy via transmission of videos rather than in-person observation.DesignWe developed an integrated smartphone and web-based system (Mobile Interactive Supervised Therapy, MIST) to provide regular medication reminders and facilitate video recording of pill ingestion at predetermined timings each day, for upload and later review by a healthcare worker. We evaluated the system in a single arm, prospective study of adherence to a dietary supplement. Healthy volunteers were recruited through an online portal. Entry criteria included age ≥21 and owning an iOS or Android-based device. Participants took a dietary supplement pill once, twice or three-times a day for 2 months. We instructed them to video each pill taking episode using the system.OutcomeAdherence as measured by the smartphone system and by pill count.Results42 eligible participants were recruited (median age 24; 86% students). Videos were classified as received—confirmed pill intake (3475, 82.7% of the 4200 videos expected), received—uncertain pill intake (16, <1%), received—fake pill intake (31, <1%), not received—technical issues (223, 5.3%) or not received—assumed non-adherence (455, 10.8%). Overall median estimated participant adherence by MIST was 90.0%, similar to that obtained by pill count (93.8%). There was a good relationship between participant adherence as measured by MIST and by pill count (Spearmans rs 0.66, p<0.001).ConclusionsWe have demonstrated the feasibility, acceptability and accuracy of a smartphone-based adherence support and monitoring system. The system has the potential to supplement and support the provision of DOT for TB and also to improve adherence in other conditions such as HIV and hepatitis C.

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. Methadone clinic—based directly observed antiretroviral therapy (DOT) has been shown to be more efficacious for improving adherence and suppressing human immunodeficiency virus (HIV) load than antiretroviral self-administration. We sought to determine whether the beneficial effects of DOT remain after DOT is discontinued. Methods. We conducted a post-trial cohort study of 65 HIV-infected opioid-dependent adults who had completed a 24-week randomized controlled trial of methadone clinic—based DOT versus treatment as usual (TAU). For 12 months after DOT discontinuation, we assessed antiretroviral adherence using monthly pill counts and electronic monitors. We also assessed viral load at 3, 6, and 12 months after DOT ended. We examined differences between DOT and TAU in (1) adherence, (2) viral load, and (3) proportion of participants with viral load of <75 copies/mL. Results. At trial end, adherence was higher among DOT participants than among TAU participants (86% and 54%, respectively; P <.001), and more DOT participants than TAU participants had viral loads of <75 copies/mL (71% and 44%, respectively; P =.03). However, after DOT ended, differences in adherence diminished by 1 month (55% for DOT vs 48% for TAU; P =.33) and extinguished completely by 3 months (49% for DOT vs 50% for TAU; P =.94). Differences in viral load between DOT and TAU disappeared by 3 months after the intervention, and the proportion of DOT participants with undetectable viral load decreased steadily after DOT was stopped until there was no difference (36% for DOT and 34% for TAU; P =.92). Conclusions. Because the benefits of DOT for adherence and viral load among HIV-infected methadone patients cease after DOT is stopped, methadone-based DOT should be considered a long-term intervention.

Background. A randomized, controlled trial was conducted to evaluate the impact of a directly administered antiretroviral therapy program (DAART) and intensive adherence case management (IACM) intervention on virologic and immunologic response to highly active antiretroviral therapy (HAART) among patients at 3 public human immunodeficiency virus clinics in Los Angeles County, California. Methods. Participants included 250 treatment-naive and treatment-experienced persons for whom no more than 1 prior HAART regimen had failed. Five days per week for 6 months, a community worker delivered 1 HAART dose to DAART participants and observed the participant take it. IACM participants met weekly with a case manager to overcome barriers to HAART adherence. A control group (the standard of care [SOC] group) received the usual care. Results. The majority of patients were Latino (64%) or African American (24%); 57% were monolingual Spanish speakers. Seventy-five percent of the patients were male, and 64% reported an annual income of <$10,000. In an intent-to-treat analysis, no statistical differences were observed in the percentage of patients with an undetectable viral load (i.e., <400 copies/mL) at 6 months between the DAART group (54%), IACM group (60%), and SOC group (54%; P > .05). An on-treatment analysis determined that there were no statistical differences in the percentage of patients with an undetectable viral load at 6 months between the DAART group (71%), IACM group (80%), and SOC group (74%; P > .05). Additionally, there were no statistical differences in 6-month changes in the CD4+ cell count or in self-reported adherence to therapy. Conclusions. Among patients with limited prior HAART experience and adherence barriers that had not been assessed before randomization, no differences were found in virologic or immunologic response for DAART or IACM, compared with SOC, at 6 months. DAART and IACM did not improve short-term outcomes when SOC included other means of adherence support that were not controlled for by the study design.

Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34-7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.