Completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV: Interim analysis of a hybrid type 3 effectiveness-implementation randomized trial.

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

Introduction

Tuberculosis (TB) is curable and preventable, yet remains a leading cause of death among people living with HIV (PLHIV) [1]. Tuberculosis preventive therapy (TPT) can reduce TB incidence and mortality by 30% to 50% [2,3] and is recommended for all PLHIV in high TB burden settings. Access to TPT has improved recently, with 3.5 million PLHIV receiving TPT in 2019 [1]. However, in many settings, less than half of those initiating TPT with the standard 6-month course of daily isoniazid complete treatment [4-6].

Safer, shorter TPT regimens are now available, including a 12-dose weekly regimen of isoniazid–rifapentine (3HP) [7-9]. In 2018, the World Health Organization (WHO) recommended 3HP as an option for TPT, citing its shortened duration as an enabler of treatment adherence and completion [1]. The Phase IV multicenter iAdhere trial conducted primarily in the United States found that 3HP treatment completion was 87.2% with directly observed therapy (DOT), 74% with self-administered therapy (SAT), and 76.4% with SAT plus short messaging service (SMS) reminders [10]. However, data on acceptance and completion of 3HP from high-burden settings—particularly in sub-Saharan Africa—remain sparse, posing a major barrier to widespread uptake and implementation [11,12]. Notably, in the iAdhere trial, noninferiority of SAT to DOT was only demonstrated among participating sites in the US, with SAT performing worst (37% treatment completion) in South Africa, the only participating African site. These findings further underscore the need for evidence of 3HP acceptability and completion in high-burden settings like Uganda. Under the recommendation of our external Trial Steering Committee and taking into account the urgent need for data from high-burden settings to support country-level decisions regarding 3HP scale-up, we undertook an interim analysis of the 3HP Options Trial, a randomized trial of 3 facilitated strategies for delivering 3HP to PLHIV receiving routine HIV/AIDS care in Uganda.

Methods

Study design and participants

The 3HP Options Trial is an ongoing 3-arm, parallel, individual participant randomized trial with a hybrid type 3 effectiveness–implementation design. Hybrid effectiveness–implementation trials assess both effectiveness and implementation outcomes, with type I designs having a greater focus on intervention effectiveness and type 3 designs having a greater focus on implementation strategies and outcomes [13]. Our overall goal as a type 3 hybrid design is to identify the optimal implementation strategy (facilitated DOT, facilitated SAT, or patient choice) for enabling completion of 3HP (i.e., the evidence-based intervention), while also adding to the large body of evidence demonstrating its safety and effectiveness. The trial is being conducted among adults accessing HIV/AIDS care at the Mulago Immune Suppression Syndrome (ISS; i.e., HIV/AIDS) clinic in Kampala, Uganda. This clinic is the largest outpatient HIV clinic in Uganda (over 16,000 PLHIV enrolled and 300 new PLHIV registered monthly), and scale-up of TPT is a key priority for clinic leadership as well as the Uganda National Tuberculosis and Leprosy Programme and AIDS Control Programme at the Uganda Ministry of Health.

Details of the trial design—including full eligibility criteria—have been published previously [14]. Briefly, the trial included adults (age ≥18 years) living with HIV engaged in care at the Mulago ISS clinic. PLHIV were excluded if they were ineligible for 3HP treatment (e.g., a baseline alanine aminotransferase [ALT] level or aspartate transaminase [AST] level >3 times the upper limit of normal) or had a logistical issue that impeded participation in the trial (e.g., unable to provide consent) (Fig 1).

Fig 1

CONSORT flow diagram.

3HP Options Trial screening, randomization, and allocation, July 13, 2020 to April 30, 2021 (n = 1,133). ALT, alanine aminotransferase; AST, aspartate transaminase; CONSORT, Consolidated Standards of Reporting Trials; INH, isoniazid; RPT, rifapentine; TB, tuberculosis.

Trial enrollment began in July 2020 and is anticipated to be completed in October 2022. The trial was approved by institutional review boards at Makerere University School of Public Health Higher Degrees, Research and Ethics Committee, the University of California, San Francisco Human Research Protection Program, and by the Uganda National Council for Science and Technology. The trial is registered on ClinicalTrials.gov (NCT03934931). Plans to report an interim analysis were reviewed and approved by the independent Trial Steering Committee.

Randomization and interventions

Briefly, eligible participants who provide written informed consent are randomized to 1 of 3 optimized delivery strategies for receiving 3HP. The delivery strategies were designed to address barriers to 3HP acceptance and completion identified in formative research [15-17] and with involvement of local stakeholders including PLHIV, clinicians, and clinic/program leadership to maximize acceptability and feasibility.

The trial protocol paper provides full details of the components of the 3 delivery strategies: facilitated DOT, facilitated SAT, and patient choice between facilitated DOT and facilitated SAT (with the assistance of a decision aid) [14]. Briefly, all strategies included (a) standardized patient counseling about the risks and benefits of 3HP; (b) streamlined clinic visits (11 visits for DOT and 2 for SAT) at the pharmacy window for symptom-based TB screening and side effects screening using a standardized checklist (S1 Text); (c) reimbursement of transport costs for clinic visits; and (d) automated interactive voice response (IVR) reminders for clinic visits. The transport reimbursement was provided by pharmacy technicians with the amount standardized based on an assessment of average local transportation costs and stakeholder assessment of programmatic feasibility at scale. For participants randomized to the facilitated DOT arm, all 3HP doses were provided at weekly clinic visits. For participants randomized to the facilitated SAT arm, the first, sixth, and final 3HP doses were directly observed at clinic visits. The remaining doses were self-administered, and participants were asked to report dosing completion using the 99DOTS platform (Everwell Health Solutions, India). 99DOTS is a low-cost digital adherence technology wherein patients call random toll-free numbers prepackaged with each medication dose, and the calls are logged on the 99DOTS server to generate a real-time dosing history that health workers can monitor [18]. The 99DOTS platform was also used to send automated weekly IVR check-in calls asking “Are you well?” to assess for potential adverse events (AEs). For participants randomized to the choice arm, a decision aid was used to offer an informed choice between the facilitated DOT and facilitated SAT strategies. The decision aid was codesigned with PLHIV to help patients prioritize their values and choose the option that best aligned with their preferences. Participants in the choice arm could switch delivery strategies at any time.

Assessments and data collection

Research staff screened PLHIV for eligibility, obtained informed consent from eligible participants, administered a baseline demographic and clinical survey, and performed randomization. Participants were then transferred to routine healthcare providers who performed all activities related to 3HP counseling, AE monitoring, dosing and adherence monitoring, and follow-up [14]. Healthcare providers did not receive any incentives or payments for delivering care related to 3HP. For AE monitoring, pharmacy technicians were asked to screen participants for potential side effects using a standardized checklist at clinic visits prior to 3HP dosing or by calling SAT participants who responded “No” to the weekly IVR check-in and to refer participants with potential side effects to a routine clinician for further evaluation. Further assessment including any laboratory testing was at the discretion of the clinician. Completion was assessed using the 99DOTS platform (i.e., weekly confirmation of self-administered doses by patient phone calls, with clinic-administered doses logged by pharmacy technicians on patients’ behalf). Self-administered doses were further verified by pharmacy technician pill count. Pharmacy technicians were asked to review participant dosing histories and call participants who missed clinic visits or did not call the 99DOTS platform to report expected self-administered doses.

To extract AE-related data, research staff retrospectively reviewed (on a weekly basis) the AEs checklist completed by pharmacy technicians and clinic charts of all participants referred to a clinician for further evaluation of a potential AE. Research staff noted whether the clinician documented the potential AE to be 3HP related and whether 3HP treatment was continued, held, or discontinued permanently. To assess 3HP initiation and completion among participants in all 3 trial arms, research staff extracted weekly 3HP dosing data from the 99DOTS server.

Trial outcomes

Trial outcomes were developed using the RE-AIM evaluation framework [19]. The primary outcome is the proportion of randomized participants who accept 3HP treatment and complete at least 11 of the 12 weekly doses within 16 weeks of enrollment [7,9,10], which reflects intervention reach (acceptance) and fidelity (treatment completion). In addition, this interim analysis assessed the proportion of participants initiating 3HP treatment who had a serious AE, defined as any AE resulting in treatment discontinuation, which reflects the effectiveness domain of the RE-AIM framework. Additional trial effectiveness and implementation outcomes are described in the published trial protocol [14] and will be reported upon completion of the trial.

Statistical analysis

Our interim analysis included simple calculation (using exact binomial 95% confidence intervals (CIs)) of outcomes aggregated across trial arms overall and stratified by sex, age, and time on ART. We used Bayesian inference to estimate the posterior probability that the proportion of PLHIV who accept and complete 3HP would exceed 0.8 under at least 1 of the 3 delivery strategies being compared (a coprimary trial hypothesis, as prespecified in the trial protocol). We used a beta distribution for the primary outcome and used a noninformative flat conjugate beta (1,1) prior. We conservatively assumed that outcomes were distributed equally across the 3 study arms; if outcomes were distributed unequally, the probability of the outcome proportion exceeding 0.8 would be higher in at least 1 arm. We then calculated the posterior probability that the proportion accepting and completing 3HP in a single arm exceeded 0.8 using standard methods taking advantage of the conjugate beta prior [20].

Results

From July 2020 through April 2021, 1,133 PLHIV accessing care at Mulago ISS clinic were screened for participation, and 226 (20%) had a contraindication to 3HP. Of the remaining 907 PLHIV who were in the target population for 3HP-based TPT, 223 (25%) were excluded for trial-specific reasons. Thus, 684 participants were randomized, and 479 participants who had exited the 16-week treatment period were included in the interim analysis (Fig 1). Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3; Table 1).

Table 1

Baseline demographic and clinical characteristics.

3HP Options Trial participants, July 13, 2020 to April 30, 2021 (n = 479).

Total randomized	N = 479
Clinical	Mean (SD), n (%)
Age	41.9 (9.2)
Female sex	309 (64.5%)
Prior TB	90 (18.8%)
On ART	479 (100.0%)
Years on ART	7.8 (4.3)
Most recent CD4 count	1,223 (2,344)
BMI (4 participants missing BMI)	26.1 (5.4)
Typical travel time to clinic (hours)	1.1 (0.7)
Sociodemographic
Employment status
Student	5 (1.0)
Not employed	57 (11.9)
Self-employed	245 (51.2)
Hired worker	47 (9.8)
Temporary/informal work	125 (26.1)
Education level
None	41 (8.6)
Primary	222 (46.4)
Secondary	175 (36.5)
Vocational training/tertiary	24 (5.0)
Postsecondary	17 (3.6)
MPI category 1
Not vulnerable to poverty	180 (37.6)
Not poor but vulnerable to poverty	182 (38.0)
Multidimensionally poor	90 (18.8)
Severely multidimensionally poor	27 (5.6)

1. The global MPI examines deprivations across 10 indicators in dimensions of health, education, and standards of living, with those deprived in one-third or more of the 10 indicators counted as being multidimensionally poor [21].

Health and education indicators are weighted at 1/6 each and standard of living indicators are weighted 1/18 each. MPI values can range from 0 to 1, with greater values indicating higher poverty. Variables included in our calculation of MPI category included (1) child mortality in the last 5 years; (2) years of schooling among household members 10 years and above; (3) school attendance among school-age children; (4) type of cooking fuel; (5) toilet type; (6) type/source of main drinking water; (7) availability of electricity; (8) type of floor material; and (9) ownership of a mobile phone, computer, or car/truck.

ART, antiretroviral therapy; BMI, body mass index; SD, standard deviation; TB, tuberculosis.

Primary outcome

In total, 445 (92.9%, 95% CI: 90.2 to 94.9) participants accepted 3HP and completed at least 11 of 12 doses within 16 weeks (Fig 2). The mean length of follow-up among those completing treatment was 78.4 days (SD: 3.5 days) and ranged from 72 days to 109 days. The longest treatment interruption among any participant reaching the primary outcome was 28 days. Treatment acceptance and completion was similarly high among men and women, younger (18 to 41 years) and older (≥42 years) participants, and participants on ART for shorter (≤1 year) and longer (>1 year) durations (Fig 2). The posterior probability that treatment acceptance and completion would exceed 0.8 under at least 1 of the 3 delivery strategies was estimated to be 99.9%.

Fig 2

3HP acceptance and completion, by subgroup.

The forest plot shows the proportion and 95% CIs of participants accepting and competing 3HP treatment (took at least 11 of 12 doses of 3HP within 16 weeks of randomization) overall and by sex, age, and time on ART. ART, antiretroviral therapy; CI, confidence interval. * Accepting and completing treatment (≥11 of 12 doses within 16 weeks).

Secondary outcomes

A total of 34 (7.1%) participants did not complete 3HP treatment. Treatment was permanently discontinued due to a suspected 3HP-related AE in 8 (1.7%) participants (4 with pruritic rash, 1 with venous thromboembolism in the right leg, 1 with flu-like syndrome and peripheral neuropathy, 1 with pulmonary embolism, and 1 with acute liver injury—see S2 Text for additional details). In addition, 2 (0.4%) participants did not initiate treatment, 21 (4.4%) were lost to follow-up (did not take at least 11 doses of 3HP within 16 weeks), 1 (0.2%) had treatment discontinued after becoming pregnant, 1 (0.2%) had treatment discontinued due to starting new medications with known 3HP drug interaction (clarithromycin, omeprazole, and domperidone), and 1 (0.2%) died in a motor vehicle accident.

Discussion

In this interim analysis of an ongoing randomized trial among PLHIV in Uganda, we found extremely high acceptance and completion of 3HP with facilitated delivery strategies that all included dosing reminders, streamlined clinic visits, and reimbursement of transport costs. This treatment was also well tolerated, with less than 2% of PLHIV discontinuing treatment due to a documented AE. Taken together, these results demonstrate high levels of 3HP uptake and completion can be achieved in the context of routine HIV/AIDS care with delivery strategies designed to address known barriers to 3HP completion.

Mounting evidence of the benefits of shorter and safer rifapentine-containing regimens [7,22,23] has led to recommendations by WHO and others to implement 3HP for global scale-up of TPT. In low-burden and/or high-income countries, 3HP completion has been reported to be similar or higher in routine healthcare settings than rates reported in controlled clinical trials [24-27]. The initial Phase IV trial of 3HP, however, demonstrated poor treatment completion in its only participating African site, particularly when self-administered (38% to 50%) [10]. Recently, Churchyard and colleagues reported that treatment completion was 90.4% for self-administered 3HP versus 50.5% for 6 months of self-administered daily isoniazid in a randomized trial among PLHIV in South Africa, Ethiopia and Mozambique [28]. This trial extends those latter findings, demonstrating that similar (if not higher) levels of treatment completion can be achieved with routine healthcare providers overseeing 3HP counseling, AEs monitoring, dosing, and adherence monitoring. These data support the recent change in the Uganda HIV prevention and treatment guidelines to recommend 3HP as an alternative to isoniazid preventive therapy [29] and may encourage similar policy decisions in other high HIV/TB burden settings.

Importantly, the results reported here were achieved with the use of facilitated delivery strategies. The strategies were designed using an implementation science-based approach to target key barriers to 3HP acceptance and completion, and local stakeholders were involved in the design process to maximize acceptability and scale up potential [14-17]. The final analysis of results from the full trial is needed to determine whether one of the strategies is more or less effective than the others. However, results from this interim analysis suggest that, when scaling up 3HP, programs should consider facilitation strategies that meet the needs and preferences of PLHIV and HIV care providers in sub-Saharan Africa [30].

This interim analysis also demonstrates how data from an ongoing randomized trial can be used to inform a time-sensitive public health question while maintaining blinding of investigators to differences between arms. Further discussion is warranted among the scientific community as to when and how interim analyses of randomized trials—particularly trials focused on improving implementation of proven interventions—should be performed to inform public health decisions.

Our analysis has some limitations. First, we only assessed outcomes aggregated across trial arms. Arm-specific details have not been provided to maintain the integrity of the ongoing trial; full trial results including comparison by arm will be presented at trial completion. Nevertheless, even when conservatively assuming that completion rates are similar across arms, our Bayesian analysis suggests a greater than 99% probability of exceeding 80% initiation and completion under at least 1 delivery strategy. Second, the trial was conducted at a single HIV/AIDS clinic in Uganda. However, the setting is similar to the US President’s Emergency Plan for AIDS Relief (PEPFAR)-funded HIV/AIDS clinics in other countries in sub-Saharan Africa, where similar barriers to completion of TPT have been widely reported [31-38]. Third, some of the facilitation strategies evaluated as part of the 3HP Options Trial are not likely to be part of usual care at most HIV/AIDS clinics in sub-Saharan Africa and would require additional funding to implement as part of 3HP scale-up. However, with increasing access to smartphones and internet in resource-limited settings, there is need for creative and inexpensive innovations to leverage this technological development to enhance health service delivery.

In conclusion, we observed extremely high acceptance and completion of 3HP for prevention of TB when delivered in a facilitated manner (i.e., with dosing reminders, streamlined visits, and reimbursement of transport costs) among PLHIV in Uganda. These interim results lend evidence to donors, policymakers, and program officials supporting the scale-up of 3HP in Uganda and elsewhere and provide some of the first data describing high 3HP completion in a high-burden setting. The findings also highlight the importance of delivering 3HP using a patient-centered approach to optimize treatment completion and thus impact on reducing the burden of TB disease and mortality among PLHIV.

CONSORT 2010 checklist of information to include when reporting a randomized trial.

CONSORT, Consolidated Standards of Reporting Trials.

(DOC)

Click here for additional data file.

StaRI: The StaRI checklist for completion.

StaRI, Standards for Reporting Implementation Studies.

(DOCX)

Click here for additional data file.

Raw deidentified data used to conduct this analysis.

Each row corresponds to a trial participant. The dataset includes 14 columns: Enrollment date; Age; Sex; BMI; On ART; Years on ART; Prior TB; One-way travel time to clinic (hours); Education level (none, primary, secondary, postsecondary (university or graduate school), or vocational/tertiary); Employment status (not employed, self-employed, temporary/informal work, hired worker, or student); MPI category (severely multidimensionally poor, multidimensionally poor but not severely, not poor but vulnerable to becoming poor, or not poor nor vulnerable to becoming poor); Outcome date; Outcome reason (completed 3HP treatment, missed 6 or more doses, stopped 3HP due to a documented AE, never initiated 3HP treatment, pregnancy, new medication with 3HP drug–drug interaction, other reason, or specify (died in a motor vehicle accident); Primary outcome (≥11 of 12 doses within 16 weeks of randomization). AE, adverse event; ART, antiretroviral therapy; BMI, body mass index; MPI, Multidimensional Poverty Index; TB, tuberculosis.

(CSV)

Click here for additional data file.

3HP Options Trial: Interim analysis statistical analysis plan.

(DOCX)

Click here for additional data file.

Options for delivering isoniazid–rifapentine (3HP) for TB prevention (3HP options implementation trial).

TB, tuberculosis.

(DOCX)

Click here for additional data file.

Side effects and symptom-based TB screening checklist.

TB, tuberculosis.

(DOCX)

Click here for additional data file.

Serious AEs summary.

AE, adverse event.

(DOCX)

Click here for additional data file.

26 Aug 2021

Dear Dr Cattamanchi,

Thank you for submitting your manuscript entitled "Completion of Isoniazid-Rifapentine (3HP) for tuberculosis (TB) prevention among people living with HIV (PLHIV): interim analysis of the 3HP Options Trial" for consideration by PLOS Medicine.

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Comments from the reviewers:

Reviewer #1: "Completion of Isoniazid-Rifapentine (3HP) for tuberculosis (TB) prevention among people living with HIV (PLHIV): interim analysis of the 3HP Options Trial" describes interim results for a randomized trial involving three arms, each investigating different therapy strategies: facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT. From 479 trial participants (approximately equally divided between the arms) having exited the treatment period, it was found that some 93% had completed the 3HP treatment, under the definition of having at least 11 of 12 doses taken within the 16-week period. This was analyzed as having a greater than 99% probability, that treatment acceptance and completion would exceed 80% under at least one of the three strategies.

The prompt addressing of curable TB is an important issue with clear benefits in mitigating death, especially amongst individuals with HIV. The 3HP randomized trial as described appears a significant contribution towards assessing treatment programmes in an African context. Additionally, the underlying raw data has also been provided as supplementary material. However, some reservations might be addressed:

1. The manuscript as it stands is fairly concise and focused. However, while the importance of the trial should not be understated, it is unclear as to whether an official publication on interim results is strictly warranted, especially as the trial is expected to complete by October 2022 (Line 103). It might be considered to support more strongly the case for publishing interim results (e.g. the trial qualifying for early stopping, in which case the analysis supporting early stopping might be presented; early stopping however does not appear to be catered for in the trial protocol, cited as [10])

2. More details or relevant citations on the Bayesian inference framework used (currently briefly described under the Statistical Analysis section from Line 134) for the main analysis, would be illuminating.

3. While Figure 2 contains primary outcome results stratified by subgroups, there does not appear analysis relating to delivery strategies (although existing results do indeed suggest that the various strategies likely result in treatment completion rates well in excess of 0.80). The Bayesian inference analysis framework might thus be explained in greater detail, and results also presented by treatment strategy (possibly also stratified by the existing subgroups in Figure 2)

4. Related to the above, the demographic characteristics in Table 1 might also be further stratified by treatment strategy, for completeness.

Reviewer #2: This manuscript presents an interim analysis of outcome data aggregated across arms of the 3HP Options trial. While the trial's primary objective is to compare different methods of delivering 3HP, the interim analysis presents treatment completion and adverse event outcomes for patients in all three arms together. A very high proportion of patients accepted and completed treatment. Given that this interim analysis does not address the question of how best 3HP can be delivered in a high-burden setting, its importance is framed as providing one of the first examples of 3HP being delivered in a programmatic setting in a high-burden country. While I agree that publishing such examples is very important, I also think that the way the authors frame this report perhaps oversimplifies the situation; my concerns on this matter are described in comments 1 and 2 below.

Specific comments:

1) The argument that this publication reflects treatment completion achieved in a programmatic setting in a high-burden setting is key to the authors' justification of its importance. However, this is a randomized trial being supported by the US NIH. I realize that "programmatic setting" is not a strictly defined term and exists on a spectrum where research is embedded within programs. But if the study paid for the digital adherence technology, staff monitoring treatment, or transport reimbursements, then it is hard to see how this is any more programmatic than the contexts of the 3HP efficacy trials, which had many sites in high-burden countries. If the authors want to make this distinction between their trial and previous trials, then I think further description is necessary about what the study supported and how this is more programmatic than previous trials.

2) Lines 91-92: I agree that data on acceptance and completion of 3HP in high-burden programmatic settings is sparse. However, I am not sure it is so sparse as to warrant omitting references to any examples or data from these settings. China has been using a twice-weekly version of 3HP programmatically (experience is reviewed in Cui et al. Management of latent tuberculosis infection in China: exploring solutions suitable for high-burden countries; other papers have been published reporting data from specific centers or studies). A program in Pakistan has been using 3HP and published on its experience (Yuen et al. Cost of delivering 12-dose isoniazid and rifapentine versus 6 months isoniazid for tuberculosis infection in a high-burden setting). The iAdhere trial whose US-specific results are mentioned in the preivous sentence incidentally also included a site in South Africa.

3) Could the authors provide a sentence or two more to describe the type of digital adherence technology used? I realize that this may be in the previous protocol paper, but since the message of this paper is that supportive systems of delivering 3HP can achieve high completion rates in a high-burden setting, I think it is important to understand exactly what those supportive systems are.

4) How was adverse event monitoring conducted? Verbal symptom screen? Was any routine laboratory monitoring performed? What evaluations were performed if patients reported signs/symptoms of a potential adverse event? I ask these questions because the secondary outcomes section reports the proportion of patients who had AE-related discontinuations, which is a very useful piece of information for programs. A description of AE monitoring would both help the reader assess the proportions being reported and also provide helpful information on how programs in high-burden settings can effectively monitor for AEs. Incidentally, if no routine laboratory monitoring was performed, it would be great if the authors could say this - one of the barriers frequently encountered to scaling up TB infection treatment in LMIC is the argument that the health system does not have the capacity for the type of LFT monitoring performed in high-income settings.

6) In the interest of making important information available to programs in high burden countries, it would be useful to know what the suspected 3HP-related adverse events were and their severity.

7) The discussion is rather abbreviated and does not delve much into discussing the supported self-administered mode of 3HP delivery, which I think is the most interesting aspect of this publication. Ultimately, the study reports an expected finding of high 3HP completion, which is consistent with the evidence from other trials, the substantial literature published by programs in low-burden settings, and the limited programmatic experience published to date from high-burden settings. To me, the value of this particular study is knowing how a program in a high-burden setting was able to achieve this high completion without DOT. Discussing this experience and comparing it to other experiences with digital adherence technology, which have been something of a mixed bag in terms of real-world effectiveness, would add great value to the paper.

Reviewer #3: The paper reports an interim analysis from a trial (3HP Options Trial) assessing the effect off three facilitated strategies of delivering 3HP regimen on treatment completion. The three study arms are facilitated DOT, facilitated SAT (including use of a digital adherence technology), and patient choice (with the assistance of a decision aid) between facilitated DOT and facilitated SAT. All participants receive automated dosing or clinic visit reminders weekly and are reimbursed transport costs for each clinic visit (11 visits for DOT & 2 for SAT).

The endpoint is treatment completion defined as accepting 3HP treatment and completing at least 11 of the 12 weekly doses within 16 weeks of enrolment. A Bayesian analysis was conducted to identify the posterior probability that at least one of the three arms will have treatment completion >80%. The analysis was based on participants randomised to 30 April 2021 with the target sample size expected to be completed in October 2022.

Introduction

1. The justification for this analysis was based on the urgent need for data in this in the context to aid in the global 3HP scaleup, particularly in Uganda. It is not clear how this aligns with Uganda policy on 3HP.

Methods

2. What is target sample size, expected to be completed in October 2022?

3. Is the trial design assessing for superiority or non-inferiority of study arms?

4. It is not clear what it meant by hybrid type 3 effectiveness-implementation design

5. How does this interim analysis relate to requests from external governance bodies such as a data safety monitoring board?

6. It is not clear how treatment completion is assessed in the three arms (doses taken at clinic visit, pill counts and /or DAT server data? ) - is the same method used across the three arms ?

7. Why is outcome of "initiating 3HP and completing at least 11 of the 12 weekly doses within 16 weeks of enrolment chosen"?

Results

8. How does the sample size in this interim analysis compare with the target sample size (expected to be completed in October 2022)?

Discussion

9. The authors concluded that "Taken together, these results demonstrate high levels of 3HP uptake and completion can be achieved in a programmatic setting when delivery strategies are designed to address known barriers to TPT completion." Given the intervention arms have varying degrees of support and therefore varying costs attached, how does this issue contribute to faster roll-out of 3HP in the region. Would be interesting for the authors to comment on whether the costing of the interventions would also influence the type of intervention to be rolled-out? Which of the three interventions will the authors be recommending to the Ministry of Health in Uganda?

10. The authors report on the recently completed trial in South Africa, Ethiopia and Mozambique which found high levels of treatment completion achieved in a programmatic context. They continue by saying that their study highlights the value of facilitated delivery deliveries - though in reality we do not know the effects of the different interventions as the interim analysis combined data across the three arms.

11. It would be useful for the authors to expand on their assertion that this ongoing analysis helped inform time critical public health questions. Are the authors recommending this type of analysis for similar scenarios?

Reviewer #4: This manuscript details an interim analysis of the ongoing 3HP Options Trial in Uganda, a randomized trial of DOT vs. SAT vs. SAT+DAT that is evaluating acceptance and completion rates across these three treatment strategies for TPT in PLHIV. Considering the need for more evidence for acceptance and adherence of these optimized strategies in the context of routine HIV care in sub-Saharan Africa, this manuscript will directly and substantially support the WHO's recommendation for using 3HP as an option for TPT in this setting.

The authors describe an inference analysis, estimating that at least one optimized treatment strategy would lead to >80% acceptance and completion of 3HP. Following their analysis, the authors demonstrated that all three strategies had a very high probability of exceeding 80% acceptance and treatment completion, effectively supporting that all three optimized strategies are highly effective in a sub-Saharan Africa context in Uganda.

The findings of this analysis are in context of previous literature on the topic, and the data analysis clearly supports the findings presented.

This manuscript details an interim analysis of an ongoing randomized trial and details of trial design have been previously published and are accessible via PubMed.

The overall study conforms to CONSORT guidelines for a randomized trial, and the methodology for the analysis to be reproduced.

Overall, the manuscript is well written, is accessible to non-specialists, and the findings will add to the body of evidence supporting high acceptability and completion rates for 3HP for TPT, using both DOT and SAT approaches, in the context of routine HIV care in sub-Saharan Africa.

Line-by-line minor comments, questions:

Line 90 - consider emphasizing that the Belknap study demonstrated that SAT was noninferior to DOT, but only specifically in the United States component of this study (further supports the authors' argument that evidence on 3HP acceptability and completion rates from studies conducted outside the United States, especially in SSA, is needed.

114 - is the digital adherence technology (DAT) text based? Consider adding explanation on what the participant was required to do with DAT. IVR is clearly explained in the manuscript.

129 - per the primary outcome: "the proportion of randomized participants who accept 129 3HP treatment and complete at least 11 of the 12 weekly doses within 16 weeks of enrollment." Did any participants who reached this outcome have a treatment interruption of 4 weeks before resuming weekly dosing and completing 3HP? I ask this as professional opinion can vary on the acceptable maximum treatment interruption allowed before a patient must restart 3HP (in my experience, between 1 and 4 weeks). Consider including the range of treatment interruption (in days) that was observed by this analysis for individuals who did successfully complete 3HP.

150 (Figure 1) - one 'did not meet inclusion criteria' in figure 1 states: "resistance to isoniazid (INH) or rifapentine (RPT) (n=2)". How was this determined/known? Were these individuals previously treated for active TB disease and now qualified for TPT? Seems that would not be the case as another 'did not meet inclusion criteria' is "prior treatment for TB/preventive TB". Please clarify.

179 - considering describing most common adverse event(s) that led to 1.7% of participants discontinuing treatment.

182 - unless it represents an increased risk for identifying the participant, consider including the name of the medication with a known 3HP interaction.

The Discussion section does not include limitations. I encourage you to discuss some possible limitations of your analysis. One plausible limitation is that this is an interim analysis of 3HP uptake for an ongoing study in Kampala, Uganda, and the acceptability and treatment completion rates observed in this setting may not reflect the probability of acceptance and completion of 3HP in other countries and settings in sub-Saharan Africa.

Overall, a well written manuscript. My recommendation is 'accept with minor revision'.

Clay Roscoe, MD MSc

HIV Services, Family Medicine Residency of Idaho, Boise, Idaho, USA

CMO, Sedia Biosciences, Beaverton, OR, USA

Reviewer #5: The authors present an interim analysis of limited data from the pragmatic randomized controlled trial, 3HP Options Trial, of the acceptance and completion (combined as a single outcome) of 3 months of weekly isoniazid and rifapentine (3HP) as TB preventive therapy (TBPT) in people living with HIV (PLHIV). The 3HP Options Trial aims to compare the acceptance, completion and costs (among other outcomes) of 3 different 3HP delivery strategies. The trial is still enrolling and the outcome data from all three arms were combined and included as an aggregate for this analysis. There is no comparator group.

TBPT can prevent TB disease in PLHIV and practical alternatives to 6 months of daily isoniazid (which is standard of care in many regions) make an important contribution to public health. 3HP has been shown to be as effective as isoniazid for this purpose and is recommended by the WHO. As the authors note, uptake in previous clinical trials has varied between 38-50% and 90%. In this analysis, the authors report high acceptance and completion of 3HP as TBTP (92.9%), and calculate that this (i.e. acceptance and completion) would exceed 80% if one of the three treatment strategies in the trial were used in this setting. These results did not vary by sex, age or time on antiretroviral therapy.

The primary outcome/s of the 3HP Options Trial will hopefully indicate a best practice for dispensing 3HP to PLHIV in Uganda. Other elements of the study design may provide a template for stakeholder and community engagement and support patient-centred care. The aggregation of the data in these analyses limits the novelty and usefulness of the results. In addition, as presented, the description of the settings and methods do not support the conclusion that the results are generalizable to a programmatic setting.

The manuscript is very well-written however, the impact is overstated. It may be better suited to an alternative publication. Given the remit that 'papers published in PLOS Medicine should be of the highest technical quality and be seen as significant advances within their own discipline and beyond' I do not think this interim analysis is suitable for publication in this journal.

Major comments

While the 3HP Options Trial may be implemented in a routine clinical setting, the trial study procedures are not routine and vary from intensive observed monitoring (with re-imbursement for visits) to digital adherence monitoring and automated dosing and clinic reminders. The implication that the results have been achieved in a programmatic context (line 198) is that they are generalizable to similar routine clinical settings in Uganda and elsewhere in sub-Saharan Africa. Such practices described above are not routine in most programs which are often under-resourced.

The authors reference the 3HP Options Trial protocol but do not describe the setting, including physical, technological and human resources. Did clinic staff receive incentives for participating in the trial management? What was the source of funds for re-imbursement? At what level was the political and management support provided? Related to the lack of detail in the methodology, streamlined clinic visits and other patient-centred (line 202) and facilitated delivery strategies (line 186) are not described but are alluded to in the discussion. In addition, one of the strengths of the study design is noted to be the engagement of relevant stakeholders (210), but this does not appear elsewhere in the manuscript (methods or results).

Minor comments

Is the trial registered?

Study design: The power calculations have been based on the parent study which aims to enrol 1656 adults. Approximately 30% of the target have been enrolled. Is this sufficient for the interim analysis to be meaningful?

As noted above, the background planning and the integration of the study procedures into the routine setting are not well described. This is necessary if the conclusion drawn is that the systems work in a program setting.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Submitted filename: Review notes.docx

Click here for additional data file.

28 Oct 2021

Submitted filename: 3HP Options Trial_Interim Analysis_Review response_final.docx

Click here for additional data file.

17 Nov 2021

Dear Dr. Cattamanchi,

Thank you very much for re-submitting your manuscript "Completion of Isoniazid-Rifapentine (3HP) for tuberculosis (TB) prevention among people living with HIV (PLHIV): interim analysis of a hybrid type 3 effectiveness-implementation randomized trial" (PMEDICINE-D-21-03667R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by five reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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Requests from Editors:

Please remove the abbreviations "TB" and "PLHIV" from the title.

Please include the baseline summary data (from lines 251-253) in your abstract.

Line 119: Please state the number of patients discontinued (8) as well as the percentage.

Please define AST and ALT in Figure 1.

Thank you for including a STARI checklist. Please adapt the checklist to use sections and paragraph numbers rather than page numbers (which will likely change during the revision process). Column headers can be updated to reflect this change (from 'page number' to 'Section name and paragraph number', or similar).

To help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your co-authors, your institution, funder, or lab.

Comments from Reviewers:

Reviewer #1: We thank the authors for acknowledging our prior concerns. The main reservation remains that this is an interim analysis with arm-specific details unable to be further provided to maintain the integrity of the ongoing trial. That said, the primary objective (i.e. a greater than 99% probability that treatment acceptance and completion would exceed 80%, under at least one of the three strategies) appear highly likely to have been attained, and the release of these interim results (as opposed to late 2023 for the full results) would appear to help guide 3HP treatment promptly. Considering this, we have in principle no objection to the release of these results if judged significant enough by the editors, particularly if the inability to reveal arm-stratified analysis is further emphasized as a limitation.

Reviewer #2: Thank you to the authors for the revision. The paper is substantially more balanced in the way it contextualizes its significance, and it is more informative for programs considering how to deliver 3HP in high-burden settings. I agree with the other reviewers who have questioned the importance of an interim results publication that neither answers the question of how best 3HP can be delivered nor discusses the implementation experience with these methods (presumably saving both for what will be the "main" trial publication). However, I think that on the balance, the information that is now presented about the use of 99DOTS, adverse event monitoring under programmatic conditions, and the use of transport reimbursements and other patient support strategies, in the context of overall high treatment completion, gives sufficient value to warrant more prompt dissemination.

The one comment I have is the added citation of the RE-AIM framework. I am sure that the larger study was indeed designed using the RE-AIM framework, but it is difficult to see how this interim report maps to it. It is not clear from the description of the trial that 3HP is the intervention and DOT/99DOTS are the implementation strategies, so it is hard to intuitively see treatment completion as a fidelity measure since it is often treated as a proxy effectiveness measure. In addition, it is confusing to cite use of the RE-AIM framework when only two of the components are addressed as a composite outcome, and the other three are not addressed at all (adoption and maintenance are not even mentioned among the outcomes referenced in the protocol). I suggest clarifying in the study design section that 3HP is the evidence-based intervention and that DOT vs supported SAT are the implementation strategies being assessed. And I suggest either briefly summarizing the main outcomes corresponding to the RE-AIM components or at the very least being explicit that this interim analysis addresses only a combined reach+implementation fidelity outcome, while the other RE-AIM components will be more fully assessed at the end of the trial.

Reviewer #3: Thank you for your detailed response to comments. My concerns have been addressed.

Reviewer #4: I very much agree with Reviewer #5's comment that this interim research, overall, may not meet full PLOS Medicine criteria for publication, which includes the language that publications "be seen as significant advances within their own discipline and beyond". As an interim analysis of 3HP TPT acceptance and completion, based on aggregated data across the study arms being evaluated, this manuscript may not fully fit PLOS Medicine criteria for publication. Though this interim analysis does not address the question of how best 3HP can be delivered in a high-burden setting (the authors do state the final research will address this), it does, importantly, provide one of the first examples of 3HP being delivered in a programmatic setting in a high-burden country, demonstrating positive acceptance and fidelity of 3HP, in general. For the latter findings, I recommend this manuscript be accepted for publication, but respectfully defer to the Editor's final decision on if this manuscript represents a significant advance in the field of TPT and meets journal criteria for publication.

Reviewer #5: Much more detail and clarity has been provided and the manuscript improved. The tone has been moderated and the data presented more appropriately (to my mind); my comments have been addressed. The manuscript is sound and well-written.

I am still not certain that the impact is sufficient for publication in PLOS MEDICINE, but the editors are better placed in this regard.

Any attachments provided with reviews can be seen via the following link:

[LINK]

23 Nov 2021

Submitted filename: 3HP Options Trial_Interim Analysis_2nd Review response.docx

Click here for additional data file.

25 Nov 2021

Dear Dr Cattamanchi,

On behalf of my colleagues and the Academic Editor, Dr Claudia Denkinger, I am pleased to inform you that we have agreed to publish your manuscript "Completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV: interim analysis of a hybrid type 3 effectiveness-implementation randomized trial" (PMEDICINE-D-21-03667R3) in PLOS Medicine.

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