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

University of California, San Francisco1,656 enrolled

Overview

The Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention (3HP Options Implementation Trial) study will be a three-arm, open-label, parallel, randomized trial. This hybrid effectiveness-implementation trial will be conducted among people living with HIV infection (PLHIV) enrolled in HIV/AIDS care at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. The overall objective of this study is to identify a patient-centered delivery strategy that will facilitate acceptance and completion of a three-month (12-dose) regimen of weekly rifapentine (RPT) and isoniazid (INH) by PLHIV enrolled in routine HIV/AIDS care in a high HIV/TB burden country. The primary outcome will be acceptance and completion of 3HP. Additional objectives will be to evaluate the implementation and cost-effectiveness of each delivery strategy.

The overall objective of this study is to identify a patient-centered strategy that will facilitate 3HP uptake by PLHIV in the context of routine HIV/AIDS care in a high HIV/TB burden country. The investigators' central hypothesis is that offering PLHIV an informed choice between directly observed therapy (DOT) and self-administered therapy (SAT) delivery strategies that are optimized to overcome key barriers to treatment adherence will result in greater acceptance and completion of 3HP. To test this hypothesis, the investigators will conduct a pragmatic randomized trial of three optimized strategies for delivering 3HP. Eligible participants will be randomized to one of three arms to receive latent tuberculosis infection (LTBI) treatment with once weekly INH and RPT for 12 weeks given by either facilitated DOT, facilitated SAT, or an informed choice between facilitated DOT and facilitated SAT (with the assistance of a decision aid tool). Primary Objective: To compare the uptake of 3HP under three delivery strategies: 1) Facilitated DOT; 2) Facilitated SAT; and 3) Informed patient choice (using a decision aid) between facilitated DOT and facilitated SAT. The primary outcome will be defined as the proportion of eligible participants who accept treatment and take at least 11 of 12 doses of RPT/INH within 16 weeks of treatment initiation. Study staff will assess medication dosing using clinic records for participants taking 3HP by DOT and using a combination of 99DOTS (Everwell Health Solutions, India) digital medication adherence technology records and pill counts at refill visits for participants taking 3HP by SAT. Secondary Objectives: 1. To estimate the costs and compare the cost-effectiveness of the three strategies for delivering 3HP. 2. To identify processes and contextual factors that influence patient acceptance and completion of 3HP under each delivery strategy. 3. To identify clinic-level barriers to adoption and implementation of 3HP under each delivery strategy. 4. To determine the proportion of patients for whom 3HP treatment is discontinued due to adverse events/intolerance. 5. To determine the cumulative 16-month incidence of active TB in each arm, categorized as definite (positive sputum Xpert MTB/RIF or culture) or probable (TB medications started at the discretion of a clinician, with evidence of subsequent improvement). 6. To determine the cumulative 28-month incidence of active TB in each arm, categorized as definite (positive sputum Xpert MTB/RIF or culture) or probable (TB medications started at the discretion of a clinician, with evidence of subsequent improvement).

Interventions

Streamlined weekly DOT visitsOTHER

Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects

Weekly DOT visit remindersOTHER

Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits

Cost reimbursement DOTOTHER

Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)

99DOTSOTHER

99DOTS-based digital adherence technology to monitor and promote adherence

Weekly SAT dosing reminders/check-insOTHER

Weekly SMS or IVR phone call dosing reminder/check-in for side effects

Cost reimbursement SATOTHER

Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * HIV-positive client engaged in care at the Mulago ISS clinic * Weight ≥40kg * Age 18 years or older * Capacity to provide informed consent in English or Luganda Exclusion Criteria: * Suspicion of active TB based on positive World Health Organization (WHO) symptom screen AND elevated point-of-care (POC) C-reactive protein (CRP), or current or planned TB treatment * Actively taking an antiretroviral medication contraindicated for use with rifapentine under contemporary WHO or Ugandan policy * Contact of a TB patient with known resistance to isoniazid or rifamycins * Women who are pregnant, breast feeding or intending to get pregnant in the next 120 days * Prisoners * Previously completed treatment for active TB or at least 6 months of isoniazid preventive therapy within past 2 years * Not intending to remain within 25 km of the Mulago ISS clinic during the study period or to receive further care at the Mulago ISS clinic * Lack of access to a mobile telephone or lack of willingness to receive SMS reminders * Pre-existing documentation of clinical liver disease. * History of sensitivity or intolerance to isoniazid or rifamycins * Another household member already enrolled in the study (household members cannot be effectively randomized to different arms) * Actively taking medication contraindicated for use with rifamycin (e.g., warfarin, phenytoin) Mixed methods and health economic sub-studies will include a subset of participants enrolled in the trial, as well as clinic administrators and clinicians (clinical officer, doctor, nurse or pharmacist) involved in 3HP delivery at the Mulago ISS clinic.

Outcomes

Primary Outcomes

Proportion of Participants Who Accepted and Completed 3HP

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.

Time frame: Within 16 weeks of treatment initiation

Secondary Outcomes

Proportion of Participants Who Accepted 3HP Treatment

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.

Time frame: Within 16 weeks of treatment initiation

Proportion of Participants Who Completed 3HP Treatment

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.

Time frame: Within 16 weeks of treatment initiation

Proportion of People Who Discontinued 3HP Treatment Due to Adverse Events/Intolerance

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

Time frame: Within 16 weeks of treatment initiation

Cumulative Incidence of Tuberculosis (TB)

Cumulative 16-month incidence of active TB in each arm

Time frame: 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 Incidence of TB

Cumulative 28-month incidence of active TB in each arm

Cost Effectiveness (Patient Perspective)

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

Time frame: At the conclusion of the study period, estimated 3 years

Cost Effectiveness (Health System Perspective)

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

Time frame: At the conclusion of the study period, estimated 3 years

Cost Effectiveness (Overall Perspective)

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

Time frame: At the conclusion of the study period, estimated 3 years

Visit Cost Reimbursement - Overall

Proportion reimbursed overall

Time frame: Through study completion, an average of 16 weeks

Visit Cost Reimbursement

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