Design

We conducted a prospective, multisite, single-arm trial in which all participants had TB treatment monitored using asynchronous VDOT. As a comparator, medical record reviews provided adherence data from a sample of patients who were monitored using in-person DOT at the same clinics. All VDOT participants used DOT for the first 2 weeks or until medication tolerance was established (whichever was longer) before initiating VDOT. Participants continued using VDOT until treatment completion or their provider switched them back to DOT.

A University of California–San Diego Institutional Review Board approved this study, as did each participating health department. Study participation did not affect treatment prescribed by participants’ physicians.

Population and Recruitment

The study population consisted of patients receiving DOT for active or suspected pulmonary TB in 3 urban (San Diego, San Francisco, Santa Clara) and 2 rural (San Joaquin, Imperial) California health jurisdictions. Patients >18 years of age with no plans to move from the jurisdiction before completing treatment and >30 days of treatment remaining were eligible. Patients with MDR TB were eligible; however, only 1.4% of California’s TB patients had MDR TB (22).

TB program staff recruited patients sequentially during routine DOT visits. Research staff explained VDOT and study procedures to interested patients and obtained written informed consent. Asynchronous VDOT was available only to study participants; patients who declined participation continued treatment through DOT. In San Diego and Santa Clara counties, synchronous VDOT was also offered to patients who were unsuitable for DOT. Two patients declined to participate before enrollment, and 5 who initially consented withdrew before starting VDOT.

Historical controls (n = 159) were group-matched by age, race or ethnicity, and sex from a random sample of patients at the 5 study sites to obtain estimates of adherence to in-person DOT. To avoid selection bias from using patients who were not offered VDOT, controls were selected from patients who completed TB treatment during the year before asynchronous VDOT introduction at each site.

VDOT Description

Figure 1

Figure 1. Schematic of asynchronous VDOT in a study assessing VDOT for monitoring tuberculosis treatment, 5 California health districts, 2015–2016. Patients use VDOT smartphone application to record a video of themselves ingesting their...

The VDOT application (Figure 1) enabled participants to record themselves swallowing each treatment dose and send videos for review by a DOT worker. Each recorded dose was automatically date- and time-stamped, encrypted, and uploaded to a secure server over a cellular or wireless network. Once the data were received by the server, the smartphone application deleted videos from the device to prevent unintentional disclosure of participant information and conserve device memory. Videos were stored on the smartphone in a manner that prevented viewing, editing, resending, or deleting them to protect participant privacy and ensure video fidelity. The asynchronous design allowed participants to take their medications regardless of network connectivity (e.g., while traveling) because videos uploaded automatically whenever cellular or WiFi connections were established. An application status screen allowed participants to see when videos were uploaded or pending. The system sent daily medication reminders by text message or email. Participants were loaned smartphones with cellular data plans to ensure that the application performed identically for all participants and avoided service outages.

TB program staff trained participants to use VDOT during routine clinic or home visits. As with DOT, whenever possible, participants were seen by staff who spoke their preferred language; otherwise, telephone-based translation services were used. Once participants demonstrated VDOT competency, they were given smartphones and instructed to record their next dose alone at the prescribed time. If the participant or DOT worker had concerns about the procedures, the DOT worker kept the phone and repeated the training during subsequent in-person DOT visits; thus, the number of training days could vary by participant. Participants also received a VDOT reference pamphlet. To minimize health risks, participants were instructed to call or visit their healthcare provider before taking medications when side effects occurred, rather than reporting side effects through videos. DOT workers regularly logged onto a password-protected website to view videos and document their observations. If expected videos were missing or videos did not clearly show participants ingesting medications, participants were contacted to identify problems and provide support as needed. Decisions about returning participants to DOT were made on a case-by-case basis rather than by using strict adherence-based criteria because some missed doses were unavoidable and requiring DOT for participants who could not meet in-person might adversely affect adherence. Routine medication refill and health monitoring visits occurred per standards of care.

Data Collection

We conducted brief (15–20 minute) baseline (before initiating VDOT) and follow-up (after ending VDOT) telephone interviews to assess sociodemographic variables, experience using mobile technology, TB history and risk factors, privacy concerns, and perceptions of TB treatment monitoring. Research staff, rather than care providers, conducted interviews to minimize response bias. Participants received $10 USD for each interview; no remuneration was paid for sending videos.

To measure treatment adherence among control patients, TB program staff reviewed their DOT records abstracting treatment start and end dates; DOT start and end dates; treatment outcome; and the number of doses expected, observed, and unobserved (i.e., self-administered, not taken, or treatment suspended). DOT was predominantly community-based and required staff travel; however, San Francisco also offered clinic-based DOT to patients who could conveniently access the clinic. Nonclinical personnel conducted most DOT visits; nurses also provided some DOT based on clinical needs and staffing considerations. Control patients were not interviewed.

VDOT versus DOT

Because VDOT was introduced after participants had initiated treatment using DOT, we calculated the fraction of expected doses observed (FEDO) while the patient was on VDOT as a measure of adherence. FEDO equals the number of observed doses divided by the sum of observed doses, missed doses, and self-administered doses. For each day that medication doses were expected, DOT workers documented whether they observed all, some, or no pills being ingested. For this analysis, doses were only considered observed if all pills were taken. If no video was received or ingestion of fewer than all pills was observed, the dose was considered missed, as were self-administered doses. Because weekend doses are not ordinarily observed in DOT, they were excluded from this calculation. FEDO was calculated for VDOT and control patients. Adherence (doses observed divided by total doses prescribed) was also computed for control patients because they used DOT throughout their treatment.

Cost Analysis

Employing a healthcare provider perspective, we used an ingredients-based, bottom-up approach (23,24) to estimate the average per-patient cost of a standard, Centers for Disease Control and Prevention–recommended (3), 6-month treatment regimen for drug-susceptible TB using DOT or VDOT. Because the likelihood of medication side effects differs between the intensive (56 daily doses) and continuation (126 daily doses) phases of treatment, costs were stratified by treatment phase and then summed to calculate the overall average patient treatment cost. Nurses from 4 sites completed a standardized questionnaire assessing personnel time, personnel salaries, and resources required to administer DOT and VDOT. Staff turnover precluded data collection from the fifth site. Completed questionnaires were discussed jointly by teleconference to ensure that all sites interpreted the questions and responded uniformly. Cost data were collected during March–June 2017 and presented in 2017 USD.

DOT personnel costs included time for patient contact, administrative tasks, and travel. VDOT personnel costs included time for community-based visits before initiating VDOT, patient VDOT training, administrative tasks, video observation, and follow-up when expected videos were not received. Some in-person observations also occurred among patients using VDOT because all patients received DOT for >2 weeks before starting VDOT and patients in San Francisco were observed in-person during weekly medication refill visits to the clinic. We converted annual salaries, including fringe benefits, into an hourly rate, assuming a 40-hour workweek. All personnel reported full-time employment. The total time for each DOT-related task (administrative, patient contact, and travel) needed to treat each patient was multiplied by the hourly rate and then summed for all personnel.

To calculate an overall per-patient travel cost, we multiplied the average number of miles per patient visit and total number of in-person visits by the current federal mileage reimbursement rate ($0.54 per mile). This approach conservatively estimated travel costs because it assumed that DOT workers used personal vehicles rather than costlier county-owned vehicles. Because DOT workers often visited multiple patients in a single outing rather than returning to the health department between each patient visit, we calculated the average number of miles per visit by dividing the average number of miles driven per day for DOT-related activities by the average number of in-person visits on any given day.

Corporate prices paid by the investigators for smartphones ($100) and service plans ($54/month) during the study were applied to all sites. An estimated VDOT application cost of $35/month/patient was applied on the basis of products commercially available at the time this article was written. Costs of antibiotics, laboratory tests, chest radiographs, and clinical examinations were excluded because they were assumed to be equivalent for VDOT and DOT.

Statistical Analysis

We used Kruskal-Wallis and Fisher exact tests to determine differences in sociodemographic characteristics, TB history, TB risk factors, and VDOT perception variables across study sites. We assessed associations between FEDO and independent variables by using Kruskal-Wallis tests (categorical variables), Wilcoxon rank sum tests (binary variables), and Spearman correlation coefficients (continuous variables). We used simple linear regression to identify factors associated with FEDO and considered significant variables (p<0.15) for inclusion in multivariable linear regression analysis. We used backward stepwise elimination to remove nonsignificant variables until only variables with p<0.05 remained in the final model and assessed normal assumption of residuals by using normal probability plot, and influential observations were assessed by residuals and Cook’s distance. We performed Wilcoxon rank sum tests to compare FEDO between VDOT and DOT and used R statistical software (25) to conduct analyses.

Participant Characteristics and VDOT Perceptions

Overall, 274 participants (248 urban and 26 rural) enrolled during October 2014–October 2015 contributed adherence and baseline interview data (Table 1). Median participant age was 44 (range 18–87) years; 61% were male, 57% were Asian, 30% were Hispanic or Latino, and 7% were white. Most (67%) were born in other countries (predominantly countries in Asia), followed by the United States (17%) and Mexico (16%). Education and income were low overall, but most participants had health insurance. Most participants (90%) owned cell phones; 72% owned smartphones. Substance use, other than smoking (42%), was uncommon, and no participants were homeless. Only race or ethnicity, education level, and country of birth differed across sites (p<0.05).

We obtained VDOT observation data from the 274 enrolled participants, 214 (78%) of whom completed follow-up interviews (Table 2). Twenty-seven percent of participants reported not sharing their VDOT experience with family members, and 66% did not share with others. Although 34% disclosed having concerns about being seen recording VDOT videos, only 8% failed to record >1 dose because of privacy concerns. At follow-up, only 2% of participants thought VDOT was less confidential than DOT, and 96% reported that VDOT was “very or somewhat easy to perform”; only 3% would choose DOT over VDOT if they had to repeat treatment, and 96% would recommend VDOT to other patients. Training VDOT procedures to participants took a median of 1 day across sites; 74% of participants required 1 day, whereas 4% needed >4 days (data not shown). Only 12 (4.4%) participants were returned to DOT before completing treatment because of poor adherence (n = 5), a lost or broken phone (n = 4), or technical or connectivity problems (n = 3).

FEDO by Treatment Monitoring Method

Figure 2

Figure 2. FEDO among patients monitored ingesting medication for tuberculosis by VDOT compared with FEDO and adherence for patients monitored using in-person DOT in a study assessing VDOT for monitoring tuberculosis treatment, 5...

Study participants used VDOT a median of 5.4 months (interquartile range [IQR] 3.5–7.1 months), generating 42,211 videos (Table 2). Median FEDO was 93.0% (IQR 83.4%–97.1%), compared with 66.4% (IQR 55.1%–89.3%) for control patients using only DOT (Figure 2). By contrast, median adherence was 100% (IQR 97.0%–100%) for control patients because of an unwavering commitment by TB program staff to ensure patients completed their treatment.

Correlates of FEDO

Median FEDO differed across individual sites (range 84.5%–96.1%; p<0.001); however, the extreme values occurred in the 2 rural sites (Table 2). Thus, FEDO did not differ between the combined urban and rural sites (92.8% vs. 94.2%; p = 0.51) in bivariate analysis (Table 3). FEDO differed by race or ethnicity and country of birth, increased with longer VDOT use and higher annual income, and decreased with marijuana use in the prior 6 months. Participants who found VDOT more difficult, more often took medications while away from home, more often had problems using the VDOT application, and more often had problems uploading videos because of poor network connectivity had lower FEDOs.

In multivariable analysis (Table 4), higher FEDO was independently associated with longer duration of VDOT use. Lower FEDO was associated with birth in Mexico or the United States compared with other countries; feeling VDOT was somewhat or very difficult compared with very easy; taking medication away from home most or every time compared with never; and having problems using VDOT more than half the time compared with “never.”

VDOT versus DOT Costs

The estimated cost for monitoring a 6-month treatment regimen using VDOT (Table 5) varied by site (range $3,031–$3,911) and was 6%–46% cheaper than community-based DOT (range $3,212–$5,788) across sites. Reduced personnel costs drove savings, which offset smartphone-related costs.