Trial Outcomes & Findings for Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention (3HP Options Implementation Trial) (NCT NCT03934931)

Results Overview

The count of eligible participants who accept treatment and take at least 11 of 12 once weekly doses of rifapentine (RPT)/isoniazid (INH) within 16 weeks of treatment initiation divided by the count of those randomized.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

1656 participants

Primary outcome timeframe

Within 16 weeks of treatment initiation

Results posted on

2025-05-11

Participant Flow

Participant milestones

Participant milestones
Measure	Facilitated Directly Observed Therapy (DOT) Facilitated directly observed therapy (DOT) arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) Facilitated self-administered therapy (SAT) participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Overall Study STARTED	552	552	552
Overall Study COMPLETED	551	552	552
Overall Study NOT COMPLETED	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Facilitated Directly Observed Therapy (DOT) Facilitated directly observed therapy (DOT) arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) Facilitated self-administered therapy (SAT) participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Overall Study Excluded as a duplicate enrollment	1	0	0

Baseline Characteristics

Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention (3HP Options Implementation Trial)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Facilitated Directly Observed Therapy (DOT) n=551 Participants Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 Participants Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=552 Participants Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Total n=1655 Participants Total of all reporting groups
Age, Continuous	42 years n=5 Participants	42 years n=7 Participants	42 years n=5 Participants	42 years n=4 Participants
Sex: Female, Male Female	378 Participants n=5 Participants	375 Participants n=7 Participants	369 Participants n=5 Participants	1122 Participants n=4 Participants
Sex: Female, Male Male	173 Participants n=5 Participants	177 Participants n=7 Participants	183 Participants n=5 Participants	533 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	551 Participants n=5 Participants	552 Participants n=7 Participants	552 Participants n=5 Participants	1655 Participants n=4 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment Uganda	551 participants n=5 Participants	552 participants n=7 Participants	552 participants n=5 Participants	1655 participants n=4 Participants
Prior Tuberculosis	104 Participants n=5 Participants	108 Participants n=7 Participants	89 Participants n=5 Participants	301 Participants n=4 Participants
Time on Antiretroviral therapy (ART)	9.0 years n=5 Participants	9.1 years n=7 Participants	9.1 years n=5 Participants	9.0 years n=4 Participants

PRIMARY outcome

Timeframe: Within 16 weeks of treatment initiation

Population: 1,656 people were eligible and randomized. One participant was erroneously re-randomized (facilitated DOT arm) after an initial enrollment; data from their second randomization was excluded. 1,655 were included in the primary outcome analysis.

The count of eligible participants who accept treatment and take at least 11 of 12 once weekly doses of rifapentine (RPT)/isoniazid (INH) within 16 weeks of treatment initiation divided by the count of those randomized.

Outcome measures

Outcome measures
Measure	Facilitated Directly Observed Therapy (DOT) n=551 Participants Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 Participants Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=552 Participants Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Proportion of Participants Who Accepted and Completed 3HP	0.946 proportion of participants	0.922 proportion of participants	0.944 proportion of participants

SECONDARY outcome

Timeframe: Within 16 weeks of treatment initiation

Population: 1,656 people were eligible and randomized. One participant was erroneously re-randomized (facilitated DOT arm) after an initial enrollment; data from their second randomization was excluded. 1,655 were included in this secondary outcome analysis.

The count of eligible people living with HIV (PLHIV) offered 3HP who accept to initiate treatment (by age, gender, CD4 stratum, viral load suppression) divided by the count of those randomized.

Outcome measures

Outcome measures
Measure	Facilitated Directly Observed Therapy (DOT) n=551 Participants Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 Participants Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=552 Participants Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Proportion of Participants Who Accepted 3HP Treatment	0.998 proportion of participants	1.00 proportion of participants	0.995 proportion of participants

SECONDARY outcome

Timeframe: Within 16 weeks of treatment initiation

Population: Those analyzed included the number of participants who took at least one dose of 3HP.

Count of participants who take at least 11 of 12 doses within 16 weeks of treatment initiation divided by the count those who take at least one dose of 3HP.

Outcome measures

Outcome measures
Measure	Facilitated Directly Observed Therapy (DOT) n=550 Participants Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 Participants Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=549 Participants Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Proportion of Participants Who Completed 3HP Treatment	0.947 proportion of participants	0.922 proportion of participants	0.949 proportion of participants

SECONDARY outcome

Timeframe: Within 16 weeks of treatment initiation

Population: Those analyzed included the number of participants who took at least one dose of 3HP.

Count of participants for whom treatment is discontinued due to adverse events or intolerance divided by the count of those who initiated 3HP.

Outcome measures

Outcome measures
Measure	Facilitated Directly Observed Therapy (DOT) n=550 Participants Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 Participants Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=549 Participants Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Proportion of People Who Discontinued 3HP Treatment Due to Adverse Events/Intolerance	0.0054 proportion of participants	0.013 proportion of participants	0.0073 proportion of participants

SECONDARY outcome

Timeframe: from date of 3HP treatment completion (11/12 doses) or once reached 16 weeks (regardless of number of doses taken) until time of active TB diagnosis or treatment initiation, death, loss to follow-up or end of the 12-month post-treatment follow-up period

Cumulative 16-month incidence of active TB in each arm

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: from date of 3HP treatment completion (11/12 doses) or once reached 16 weeks (regardless of number of doses taken) until time of active TB diagnosis or treatment initiation, death, loss to follow-up or end of the 24-month post-treatment follow-up period

Cumulative 28-month incidence of active TB in each arm

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At the conclusion of the study period, estimated 3 years

The incremental patient cost per disability-adjusted life year (DALY) averted.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At the conclusion of the study period, estimated 3 years

The incremental health system cost per disability-adjusted life year (DALY) averted.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At the conclusion of the study period, estimated 3 years

Incremental cost of each delivery strategy per disability adjusted life year (DALY) averted.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Through study completion, an average of 16 weeks

Proportion reimbursed overall

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks

Proportion reimbursed on the same day as each 3HP clinic visit

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks

Mean number of minutes for each DOT/refill visit

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks

Median number of minutes for each DOT/refill visit

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: The day before each 3HP clinic visit throughout study completion, an average of 16 weeks

Proportion of SMS or IVR phone call reminders delivered to participants for clinic visits

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks

Proportion of participants screened for active TB during DOT or refill visits

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks

Proportion of participants screened for side effects during DOT or refill visits.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each scheduled dose throughout study completion, an average of 16 weeks

Proportion of doses confirmed using digital adherence technology. Doses directly observed (i.e., during initial or refill visits) will not be included in the denominator.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: The day before each scheduled dose throughout study completion, an average of 16 weeks

Proportion of SMS or IVR phone call reminders delivered to participants for medication dosing

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On the same day as each scheduled dose throughout study completion, an average of 16 weeks

Proportion of weekly SMS or IVR phone call check-ins delivered to participants

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 24 hours after missed scheduled dose throughout study completion, an average of 16 weeks

Proportion of SMS or IVR phone call reminders delivered to participants following missed doses

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 24 hours after missed scheduled appointment throughout study completion, an average of 16 weeks

Proportion of SMS or IVR phone call reminders delivered to participants following missed appointments

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 24 hours after negative response throughout study completion, an average of 16 weeks

Proportion of participants who receive appropriate follow-up (phone call or home visit) for lack of response/negative response to weekly check-in SMS or IVR phone call

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Through study completion, an average of 16 weeks

Mean total participant costs related to TB preventive care services

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Through study completion, an average of 16 weeks

Mean score on participant satisfaction questionnaire

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At the conclusion of the study period, estimated 3 years

Thematic interpretation of provider- and clinic-level barriers to care from provider focus group discussions.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Through study completion, an average of 16 weeks

Thematic interpretation of barriers to 3HP completion from patient interviews

Outcome measures

Outcome data not reported

Adverse Events

Facilitated Directly Observed Therapy (DOT)

Serious events: 3 serious events

Other events: 83 other events

Deaths: 1 deaths

Facilitated Self-Administered Therapy (SAT)

Serious events: 7 serious events

Other events: 86 other events

Deaths: 0 deaths

Patient Choice Between Facilitated DOT and Facilitated SAT

Serious events: 4 serious events

Other events: 76 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Facilitated Directly Observed Therapy (DOT) n=551 participants at risk Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 participants at risk Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=552 participants at risk Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
Skin and subcutaneous tissue disorders Generalized pruritus/skin rash	0.36% 2/551 • Number of events 2 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Ear and labyrinth disorders Hearing impairment	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Hepatobiliary disorders Liver injury	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Gastrointestinal disorders Gastritis	0.18% 1/551 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Vascular disorders Pulmonary embolism	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
General disorders 3HP-related hypersensitivity	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.36% 2/552 • Number of events 2 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
General disorders Flu-like syndrome	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Eye disorders Toxic Conjunctivitis	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Blood and lymphatic system disorders Venous thromboembolism	0.00% 0/551 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.00% 0/552 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	0.18% 1/552 • Number of events 1 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist

Other adverse events

Other adverse events
Measure	Facilitated Directly Observed Therapy (DOT) n=551 participants at risk Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)	Facilitated Self-Administered Therapy (SAT) n=552 participants at risk Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment. 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)	Patient Choice Between Facilitated DOT and Facilitated SAT n=552 participants at risk Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded. Streamlined weekly DOT visits: Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects Weekly DOT visit reminders: Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits Cost reimbursement DOT: Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12) 99DOTS: 99DOTS-based digital adherence technology to monitor and promote adherence Weekly SAT dosing reminders/check-ins: Weekly SMS or IVR phone call dosing reminder/check-in for side effects Cost reimbursement SAT: Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)
General disorders Fever	3.4% 19/551 • Number of events 21 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	3.8% 21/552 • Number of events 25 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	3.1% 17/552 • Number of events 19 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Nervous system disorders Headache	4.2% 23/551 • Number of events 23 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	4.3% 24/552 • Number of events 29 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	2.9% 16/552 • Number of events 16 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
General disorders Weakness	3.6% 20/551 • Number of events 20 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	3.6% 20/552 • Number of events 21 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	2.5% 14/552 • Number of events 14 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist
Musculoskeletal and connective tissue disorders Joint pain	3.8% 21/551 • Number of events 24 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	3.8% 21/552 • Number of events 26 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist	5.3% 29/552 • Number of events 33 • Adverse events were collected weekly over the course of 3HP treatment duration (up to 16 weeks after treatment initiation) Adverse Events (AE) pre-specified to be reported according to participant randomization; AEs were not reported with respect to the specific intervention received by the participant in the "Patient Choice Between Facilitated DOT and Facilitated SAT" Arm, only the randomization group. Facilitated DOT: weekly in-person by pharmacy technician using standard checklist. Facilitated SAT: dose 2-5 \& 7-11: two-way interactive voice response phone calls; dose 6 \& 12: in-person using standard checklist

Additional Information

Professor Adithya Cattamanchi

University of California Irvine

Phone: 415-206-5489

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place