Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial

Fred C Semitala; Jillian L Kadota; Allan Musinguzi; Fred Welishe; Anne Nakitende; Lydia Akello; Lynn Kunihira Tinka; Jane Nakimuli; Joan Ritar Kasidi; Opira Bishop; Suzan Nakasendwa; Yeonsoo Baik; Devika Patel; Amanda Sammann; Payam Nahid; Robert Belknap; Moses R Kamya; Margaret A Handley; Patrick PJ Phillips; Anne Katahoire; Christopher A Berger; Noah Kiwanuka; Achilles Katamba; David W Dowdy; Adithya Cattamanchi

doi:10.1371/journal.pmed.1004356

. 2024 Feb 20;21(2):e1004356. doi: 10.1371/journal.pmed.1004356

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial

Fred C Semitala ^1,^2,^3,^‡, Jillian L Kadota ^4,^5,^‡, Allan Musinguzi ², Fred Welishe ², Anne Nakitende ², Lydia Akello ², Lynn Kunihira Tinka ², Jane Nakimuli ², Joan Ritar Kasidi ², Opira Bishop ², Suzan Nakasendwa ⁶, Yeonsoo Baik ⁷, Devika Patel ⁸, Amanda Sammann ⁸, Payam Nahid ^4,⁵, Robert Belknap ⁹, Moses R Kamya ^1,², Margaret A Handley ^10,¹¹, Patrick PJ Phillips ^4,⁵, Anne Katahoire ¹², Christopher A Berger ^4,⁵, Noah Kiwanuka ⁶, Achilles Katamba ^13,¹⁴, David W Dowdy ^14,^15,^‡, Adithya Cattamanchi ^4,^14,^16,^‡,^*

Editor: Claudia M Denkinger¹⁷

¹Makerere University, Department of Medicine, College of Health Sciences, Kampala, Uganda

²Infectious Diseases Research Collaboration, Kampala, Uganda

³Makerere University Joint AIDS Program, Kampala Uganda

⁴Center for Tuberculosis, University of California San Francisco, San Francisco, California, United States of America

⁵Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America

⁶Department of Epidemiology and Biostatistics, School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda

⁷Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

⁸The Better Lab and Department of Surgery, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America

⁹Denver Health and Hospital Authority and Division of Infectious Diseases, Department of Medicine, University of Colorado, Denver, Colorado, United States of America

¹⁰Center for Vulnerable Populations, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America

¹¹Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America

¹²Child Health and Development Center, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda

¹³Clinical Epidemiology & Biostatistics Unit, Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda

¹⁴Uganda Tuberculosis Implementation Research Consortium, Walimu, Kampala, Uganda

¹⁵Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America

¹⁶Division of Pulmonary Diseases and Critical Care Medicine, University of California Irvine, Irvine, California, United States of America

¹⁷UniversitatsKlinikum Heidelberg, GERMANY

A.S. and D.P. are human-centered design consultants for The Empathy Studio, LLC. D.P. is a human-centered design consultant for the Diversity Innovation Hub at Mt. Sinai. The other authors have declared that no competing interests exist.

‡ FCS and JLK share first authorship on this work. DWD and AC are joint senior authors on this work.

^✉

* E-mail: Adithya.cattamanchi@uci.edu

Roles

Fred C Semitala: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

Jillian L Kadota: Data curation, Formal analysis, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Allan Musinguzi: Data curation, Methodology, Project administration, Supervision, Writing – review & editing

Fred Welishe: Data curation, Writing – review & editing

Anne Nakitende: Data curation, Writing – review & editing

Lydia Akello: Data curation, Writing – review & editing

Lynn Kunihira Tinka: Data curation, Writing – review & editing

Jane Nakimuli: Data curation, Writing – review & editing

Joan Ritar Kasidi: Data curation, Writing – review & editing

Opira Bishop: Data curation, Writing – review & editing

Suzan Nakasendwa: Formal analysis, Visualization, Writing – review & editing

Yeonsoo Baik: Formal analysis, Methodology, Visualization, Writing – review & editing

Devika Patel: Methodology, Writing – review & editing

Amanda Sammann: Investigation, Methodology, Writing – review & editing

Payam Nahid: Conceptualization, Investigation, Methodology, Writing – review & editing

Robert Belknap: Conceptualization, Investigation, Methodology, Writing – review & editing

Moses R Kamya: Conceptualization, Investigation, Methodology, Writing – review & editing

Margaret A Handley: Conceptualization, Investigation, Methodology, Writing – review & editing

Patrick PJ Phillips: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – review & editing

Anne Katahoire: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

Christopher A Berger: Investigation, Methodology, Project administration, Writing – review & editing

Noah Kiwanuka: Conceptualization, Formal analysis, Investigation, Methodology, Visualization, Writing – review & editing

Achilles Katamba: Conceptualization, Investigation, Methodology, Project administration, Resources, Supervision, Writing – review & editing

David W Dowdy: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Adithya Cattamanchi: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Claudia M Denkinger: Academic Editor

PMCID: PMC10914279 PMID: 38377166

Abstract

Background

Expanding access to shorter regimens for tuberculosis (TB) prevention, such as once-weekly isoniazid and rifapentine taken for 3 months (3HP), is critical for reducing global TB burden among people living with HIV (PLHIV). Our coprimary hypotheses were that high levels of acceptance and completion of 3HP could be achieved with delivery strategies optimized to overcome well-contextualized barriers and that 3HP acceptance and completion would be highest when PLHIV were provided an informed choice between delivery strategies.

Methods and findings

In a pragmatic, single-center, 3-arm, parallel-group randomized trial, PLHIV receiving care at a large urban HIV clinic in Kampala, Uganda, were randomly assigned (1:1:1) to receive 3HP by facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid. We assessed the primary outcome of acceptance and completion (≥11 of 12 doses of 3HP) within 16 weeks of treatment initiation using proportions with exact binomial confidence intervals (CIs). We compared proportions between arms using Fisher’s exact test (two-sided α = 0.025). Trial investigators were blinded to primary and secondary outcomes by study arm. Between July 13, 2020, and July 8, 2022, 1,656 PLHIV underwent randomization, with equal numbers allocated to each study arm. One participant was erroneously enrolled a second time and was excluded in the primary intention-to-treat analysis. Among the remaining 1,655 participants, the proportion who accepted and completed 3HP exceeded the prespecified 80% target in the DOT (0.94; 97.5% CI [0.91, 0.96] p < 0.001), SAT (0.92; 97.5% CI [0.89, 0.94] p < 0.001), and Choice (0.93; 97.5% CI [0.91, 0.96] p < 0.001) arms. There was no difference in acceptance and completion between any 2 arms overall or in prespecified subgroup analyses based on sex, age, time on antiretroviral therapy, and history of prior treatment for TB or TB infection. Only 14 (0.8%) participants experienced an adverse event prompting discontinuation of 3HP. The main limitation of the study is that it was conducted in a single center. Multicenter studies are now needed to confirm the feasibility and generalizability of the facilitated 3HP delivery strategies in other settings.

Conclusions

Short-course TB preventive treatment was widely accepted by PLHIV in Uganda, and very high levels of treatment completion were achieved in a programmatic setting with delivery strategies tailored to address known barriers.

Trial Registration

ClinicalTrials.gov NCT03934931.

Fred C. Semitala and colleagues compared three delivery strategies for the completion of Isoniazid-Rifapentine for tuberculosis prevention among people living with HIV in Uganda.

Author summary

Why was this study done?

There is limited evidence on strategies that achieve high acceptance and completion of tuberculosis (TB) preventive treatment in the context of routine HIV/AIDS care, despite recommendations from the World Health Organization for its scale-up in high-burden HIV/TB settings.
Two previous implementation trials have assessed delivery of 12 weeks of isoniazid and rifapentine (3HP) by self-administered therapy (SAT) in high-burden settings and found variable completion rates. In both studies, 3HP dosing and treatment supervision were conducted by research staff rather than by routine health workers.

What did the researchers do and find?

In a pragmatic trial,1,655 people living with HIV (PLHIV) at a high-volume clinic in Kampala, Uganda, received 3HP either by facilitated directly observed therapy (DOT) involving a pharmacy technician, facilitated SAT, or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid.
We found high levels of 3HP completion in the context of routine HIV/AIDS care.
The high treatment completion rates were independent of 3HP delivery strategy.

What do these findings mean?

High levels of 3HP treatment completion are achievable in routine programmatic settings when delivery strategies are optimized to overcome known barriers.
A limitation of the study is that it was conducted at a single center. Further studies are needed to confirm the findings and the feasibility of the facilitation strategies in other settings.

Introduction

Tuberculosis (TB) is a curable and preventable disease but remains a leading cause of death worldwide, especially among people living with HIV (PLHIV) [1]. TB preventive treatment (TPT) can reduce TB incidence by 30% to 50% [2] and the risk of death or severe illness by 35% among PLHIV [3]. Scaling up TPT is crucial to the END TB Strategy and global coverage has improved, particularly among PLHIV [4,5]. However, a recent study estimated completion of the conventional 6 to 9 months of daily isoniazid TPT regimen among PLHIV in 16 high-burden countries to be 66% overall and under 50% in 4 of the countries [6].

Short-course regimens for TB prevention, such as 3HP (once-weekly isoniazid and rifapentine for 12 weeks), are now available. The World Health Organization (WHO) recommends 3HP as an alternative to daily isoniazid, citing its shortened treatment duration, equivalent efficacy for TB prevention, and better tolerability and safety [7,8]. However, evidence remains limited on how to effectively deliver 3HP in a manner that achieves high acceptance and completion in real-world settings. In 2 previous implementation trials [9,10], trained research staff provided 3HP, rather than integrating it into routine care, and one found low (38%) completion rates with self-administered therapy at the only sub-Saharan African site included [9].

To assist National TB Programs in planning 3HP scale-up, we conducted the 3HP Options Trial. This pragmatic, 3-arm, type 3 hybrid effectiveness-implementation randomized trial [11] aimed to evaluate 3 facilitated strategies for delivering 3HP to PLHIV within routine HIV/AIDS care [12]. Our coprimary hypotheses were that, in a high HIV/TB burden setting, the proportion of PLHIV accepting and completing 3HP could exceed 80%, and this proportion would be highest among PLHIV randomized to the informed choice arm.

Methods

Ethics statement

The study protocol [12] was approved by ethical committees at the University of California San Francisco and Makerere University. Written informed consent was obtained from all study participants. An independent trial steering committee periodically oversaw trial conduct and approved protocol changes (registered at clinicaltrials.gov, NCT03934931).

Study design and participants

We conducted this pragmatic, single-center, 3-arm, parallel-group randomized trial at the Mulago Immune Suppression Syndrome (HIV/AIDS) clinic in Kampala, Uganda. Eligible participants included PLHIV aged 18 years or older, receiving HIV/AIDS care at the clinic, and candidates for 3HP-based TB preventive treatment (S1 Text). We excluded people weighing <40 kilograms (as 3HP was not weight adjusted), initiating antiretroviral therapy (ART) within the previous 3 months, with documented clinical liver disease or history of alcohol abuse, with baseline serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level exceeding 3 times the upper limit of normal, not intending to stay within 25 kilometers of the study clinic (to enable follow-up), without access to a mobile telephone or not willing to receive phone-based reminders (which would interfere with the facilitated self-administered therapy delivery strategy), or living with another household member already enrolled in the study.

Potential participants were recruited from the clinic waiting area through peer health educators or clinic providers. Interested PLHIV were referred to research staff for eligibility confirmation and written informed consent. The study design and results are reported following CONSORT 2010 guidelines [13].

Randomization and masking

Participants were randomly assigned (1:1:1) to receive 3HP through facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT (Fig 1). Random permuted blocks of variable size (9, 12, and 15) with equal allocation were generated by the trial statistician. Sealed opaque envelopes containing individual random assignments were given to study nurses in multiple batches to minimize predictability. After informed consent, each participant selected and opened the top-most envelope to reveal their randomization assignment. Due to the intervention nature, participants and study staff were not masked to arm assignment. However, minimal interaction occurred between study staff and participants after enrollment; routine clinic staff provided 3HP doses, screened for adverse effects and made decisions about holding or discontinuing 3HP treatment. Throughout the trial, the principal investigators remained masked to randomization assignments.

Fig 1 — INH/RPT, isoniazid/rifapentine; 3HP, once-weekly isoniazid and rifapentine for 12 weeks.

Interventions

Methods by which the delivery strategies were conceptualized, including results from formative research conducted with key local and national stakeholders, are detailed elsewhere [12,14–16]. Briefly, we used theory-informed frameworks, human-centered design (HCD) methods, and person-centered care principles to optimize 3HP delivery by SAT and DOT to address key capability, opportunity, and motivation barriers [17].

Facilitation strategies in all arms included standardized counseling and transport reimbursement for clinic visits. The value of transport reimbursement varied ($5 to $10 USD) based on COVID-19 impacts on public transportation costs during the study period. 3HP was provided using loose pills (six 150 mg rifapentine tablets, three 300 mg isoniazid tablets, and two 25 mg pyridoxine tablets) for the first 4 months of the trial and using fixed-dose combination pills (3 rifapentine 300 mg/isoniazid 300 mg tablets and two 25 mg pyridoxine tablets) for the remainder of the trial. Unique components of each delivery strategy are described below.

Facilitated DOT

Participants returned to the clinic pharmacy window weekly on their preferred day and time for a streamlined pharmacy visit, without the need to wait in the general queue. During each visit, a clinic pharmacy technician screened them for adverse events and TB symptoms (referring those who screened positive to a clinician), observed 3HP dose ingestion, and recorded dosing. The day prior to each weekly appointment, participants received a short, one-way automated interactive voice response (IVR) phone call (at no cost to participants) that included a motivational message that changed each week and a reminder to return to the clinic for their appointment. If the clinic appointment was missed, the one-way IVR message was repeated for up to 3 consecutive days.

Facilitated SAT

Participants received a pill pack codesigned with PLHIV using an HCD process [12]. The pill pack included individual plastic bags containing each weekly dose that contained (1) the correct number of 3HP pills for that week’s dose and (2) a card insert displaying a motivational message and a unique toll-free phone number participants were instructed to call after taking their weekly dose to confirm dosing. Once the number was called, the 99DOTS (Everwell Health Solutions, Bengaluru, India) platform automatically reflected the dose as taken and an individualized adherence calendar could be remotely accessed and monitored by clinic pharmacy technicians for 3HP adherence (S1 and S2 Figs). Participants were asked to return to the clinic for the sixth and 12th doses for pill counts, in-person dosing, and assessment of side effects. The day prior to their expected next dose, participants received a two-way automated IVR phone call that included a motivational message, a reminder to take their weekly dose, and the question “Are you well?”, which enabled participants to respond affirmatively or negatively using the phone keypad. The IVR message was repeated for up to 3 consecutive days if there was no confirmation of dosing using the toll-free number. Pharmacy technicians were asked to call participants who reported feeling unwell to the two-way IVR message to conduct further assessments.

Informed choice

A research nurse used a counselling flipbook to provide a brief descriptive overview of facilitated DOT and facilitated SAT. Participants were then asked to state their preferred option considering their lifestyle and values with respect to 7 key concepts related to 3HP delivery (time, cost, provider interaction, side effect monitoring, travel, stigma, and work schedule), a decision-making process that was guided by a shared decision-making tool (flipbook). Following this process, the study nurse would review the stated preferences with the participant and ask for their final informed choice of delivery strategy, reminding them that they had the option to switch strategies at any point if desired.

Data collection

Baseline demographic and clinical surveys were administered to all participants before their first 3HP dose. A completion survey was conducted during the final dose visit. 3HP dosing information was extracted from the 99DOTS server. Routine clinic staff, with no extra training, performed all other study procedures. No study-related attempts were made to contact participants for missed doses or adverse events. Both study and clinic staff logged weekly time requirements for their duties, and clinical activities were observed using time-and-motion surveys. Time data were transferred to human resource cost based on the national average level of each type of staff’s hourly salary. Study staff completed monthly budgetary reviews of bills and receipts for resource-use data, including overhead costs, study drugs, drug import fees, office supplies, internet charges, and lab consumables. Cost of transport reimbursement was calculated based on the total number of patients and their number of visits in each arm.

Outcomes

The primary outcome measured the reach (acceptance) and fidelity (treatment completion) of 3HP, defined as the proportion of participants who took at least 1 dose of 3HP (acceptance) and completed at least 11 of 12 doses of 3HP within 16 weeks of treatment initiation (completion) [7,9,10]. Prespecified subgroup analyses included age group, sex, time on ART, and prior TB or TB infection treatment experience. Prespecified secondary outcomes were 3HP acceptance (taking at least 1 dose) and 3HP completion among those who accepted (prespecified as the trial per-protocol analysis). Additional prespecified secondary outcomes reported here include the following: adverse events leading to 3HP discontinuation, the fidelity of intervention and delivery strategy implementation (reimbursement metrics, time spent at clinical visits/time spent on 3HP-related activities, time spent completing the shared decision-making tool, proportion of IVR check-in calls, dosage reminders, and appointment reminders sent, proportion of participants who received follow-up/support actions following response to IVR check-ins or missed appointments/doses, and proportion of doses confirmed using the 99DOTS platform), the acceptability of delivery strategies (median scores for domains within the patient satisfaction questionnaire regarding services received throughout the course or 3HP treatment, median scores for domains within the shared decision-making questionnaire regarding the shared decision-making process), and the per-patient cost of 3HP delivery from the health system perspective. Additional secondary outcomes that will be reported separately include cost-effectiveness, patient costs, thematic results from patient and healthcare provider in-depth and key informant interviews, self-reported patient barriers to TB preventive services, provider- and clinic-level barriers to 3HP delivery, and data on active TB screening and TB incidence up to 2 years posttreatment [12]. Data on efficacy endpoints are still being collected.

Statistical analysis

We estimated sample size based on a minimum clinically important difference of 10% in 3HP acceptance and completion between DOT and informed choice arms, which is consistent with previous implementation trials of 3HP delivery strategies [9]. To be conservative, we applied a Bonferroni correction for 2 independent comparisons (DOT versus Choice and SAT versus Choice). Assuming 10% loss between consent and allocation, we determined that 552 participants per arm (N = 1,656 total) would achieve 90% power (two-sided α = 0.025). This sample size also provided 85% power to detect a point estimate of at least 80% 3HP acceptance and completion in the Choice arm, assuming a true level of 85%.

Following our prespecified statistical analysis plan (S2 Text), we calculated 3HP acceptance and completion in each arm as a proportion with exact binomial confidence interval (CI). To achieve the target of at least 80% acceptance and completion, we assessed whether the lower bound of the Bonferroni-corrected 97.5% CI exceeded 0.80 in any of the 3 arms. All participants were analyzed in the treatment arms to which they were randomized. We compared proportions between arms by calculating unadjusted prevalence ratios and using Fisher’s exact test to determine statistical significance (two-sided α = 0.025). As per our statistical analysis plan, we conducted an as-treated analysis, where participants in the Choice arm were allocated to the DOT or SAT arm based on their initial choice of strategy, and the DOT and SAT arms were compared using the same approach described above. We estimated the total per-patient cost of each delivery strategy from the health system perspective by compiling cost data from time and motion surveys, weekly time logs, and monthly budgetary reviews. Costs were estimated in 2021 Ugandan Shillings and converted to US dollars using the average exchange rate in 2021 (1 USD = 3,587.05 USh) [18].

All statistical analyses were performed using Stata version 16 (Stata Corporation, USA).

Results

Of 2,813 PLHIV screened between July 13, 2020, and July 8, 2022, 1,656 were eligible and randomized. Follow-up continued until September 29, 2022. One participant was erroneously rerandomized (facilitated DOT arm) after an initial enrollment; data from their second randomization was excluded. Median participant age was 42 years (interquartile range [IQR]: 36 to 48); 1,122 (67.8%) were female; and median ART experience was 9.0 years (IQR: 5.6 to 12.5). Baseline characteristics were balanced across study arms (Table 1). In the Choice arm, 370 participants (67.0%) initially preferred facilitated DOT. Choice of delivery strategy did not differ across educational strata or age; however, males were more likely than females to choose DOT (S1 Table). During 3HP treatment, 11 Choice participants switched strategies (4 from SAT to DOT, 6 from DOT to SAT, 1 from DOT to SAT, then back to DOT).

Table 1. Participant baseline characteristics, by study arm (N = 1,655)^a.

	Facilitated DOT	Facilitated SAT	Informed Choice
	(N = 551)	(N = 552)	(N = 552)
Initial choice of delivery strategy
Facilitated DOT	-	-	370 (67.0%)
Facilitated SAT	-	-	182 (33.0%)
Age	42 (36–48)	42 (36–48)	42 (36–48)
Female sex	378 (68.6%)	375 (67.9%)	369 (66.9%)
Education
None	34 (6.2%)	56 (10.1%)	49 (8.9%)
Primary	271 (49.2%)	245 (44.4%)	266 (48.2%)
Secondary	209 (37.9%)	201 (36.4%)	190 (34.4%)
Tertiary/Vocational	20 (3.6%)	32 (5.8%)	33 (6.0%)
University/Graduate School	17 (3.1%)	18 (3.3%)	14 (2.5%)
Employment status ^b
Unemployed	65 (11.8%)	63 (11.4%)	63 (11.5%)
Hired worker	143 (26.1%)	135 (24.5%)	119 (21.8%)
Self-employed worker	293 (53.4%)	311 (56.3%)	312 (57.1%)
Other	48 (8.7%)	43 (7.8%)	52 (9.5%)
Household size	4 (2–5)	4 (3–5)	4 (2–5)
Multidimensional Poverty Index ^c
Not vulnerable to multidimensional poverty	231 (41.9%)	252 (45.7%)	236 (42.8%)
Vulnerable to multidimensional poverty	199 (36.1%)	190 (34.4%)	194 (35.1%)
Multidimensionally poor	94 (17.1%)	93 (16.9%)	98 (17.8%)
Severely multidimensionally poor	27 (4.9%)	17 (3.1%)	24 (4.4%)
Travel time (minutes) to clinic	65 (40–105)	60 (40–90)	60 (39.5–90)
Prior treatment for tuberculosis (TB) or TB infection	104 (18.9%)	108 (19.6%)	89 (16.1%)
Time (years) on ART	9.0 (5.8–12.4)	9.1 (5.6–12.5)	9.1 (5.5–12.7)
ART regimen
Dolutegravir + Lamivudine + Tenofovir	482 (87.5%)	489 (88.6%)	480 (87.0%)
Tenofovir + Lamivudine + Efavirenz	40 (7.3%)	29 (5.3%)	43 (7.8%)
Other^d	29 (5.3%)	34 (6.2%)	29 (5.3%)
CD4⁺ T cell count (cells/μL)^e	495 (325–682)	447.5 (294–633)	471 (332–656)
Viral load <1,000 copies/mL ^f	541 (98.2%)	545 (98.7%)	547 (99.1%)
Body Mass Index (kg/m ² )	25.4 (21.6–28.9)	25.3 (22.2–29.5)	24.9 (22.0–29.3)

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ART, antiretroviral therapy; DOT, directly observed therapy; MPI, multidimensional poverty index; SAT, self-administered therapy; TB, tuberculosis.

^aData are n (%) or median and interquartile range (IQR).

^bn = 8 missing (DOT: n = 2; SAT: n = 0; Choice: n = 6).

^cThe 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. MPI scores can range from 0 to 1 and are classified as not vulnerable to multidimensional poverty (MPI score: 0–0.19), vulnerable to multidimensional poverty (MPI score: 0.20–0.32), multidimensionally poor (MPI score: 0.33–0.49), and severely multidimensionally poor (MPI score: ≥0.50).

^dOther regimens included Abacavir + Lamivudine + Dolutegravir (n = 82), Lamivudine + Zidovudine + Dolutegravir (n = 8), Lamivudine and Zidovudine 150 mg/300 mg tablet (n = 1), Abacavir + Lamivudine + Efavirenz (n = 1).

^en = 30 missing (DOT: n = 5; SAT: n = 14; Choice: n = 11).

^fNot detected defined as <1,000 copies/mL according to Ugandan guidelines; n = 2 missing (DOT: n = 1; SAT: n = 1; Choice: n = 0).

Among the 1,655 PLHIV included in the primary analysis, 81 (4.9%) participants who initiated 3HP completed fewer than 11 doses within the allotted 16-week treatment period and were classified as not reaching the primary outcome. Posttreatment survey data among a sample (n = 73) of these 81 participants suggested side effects, transport, and work-related challenges were the most important barriers (S2 Table). Additionally, 23 (1.4%) other participants did not accept or complete 3HP treatment, including 18 for whom a routine clinician discontinued 3HP due to adverse events (N = 14), pregnancy (N = 2), drug–drug interaction (N = 1), or COVID-19 (N = 1); 4 who never initiated 3HP; and 1 who died for reasons unrelated to the trial.

The proportion of participants who accepted and completed 3HP exceeded 0.80 for all 3 delivery strategies (p < 0.001): 521 participants in both the facilitated DOT (0.95; 97.5% CI [0.92, 0.97]) and Choice arms (0.94; 97.5% CI [0.92, 0.96]), and 509 (0.92; 97.5% CI [0.89, 0.95]) in the facilitated SAT arm (Fig 2). We found no evidence that the proportion accepting and completing 3HP differed when comparing SAT to DOT (prevalence ratio [PR] 0.98; 97.5% CI [0.94, 1.01] p = 0.118), Choice to DOT (PR 1.00; 97.5% CI [0.97, 1.03] p = 0.901), or Choice to SAT (PR 1.02; 97.5% CI [0.99, 1.06] p = 0.149) (Fig 3).

Fig 2 — The primary outcome of 3HP acceptance and completion was defined as the proportion of participants who took at least 11 of 12 doses of 3HP within 16 weeks of treatment initiation. Secondary outcomes included 3HP acceptance, defined as the proportion of participants who took at least 1 dose of 3HP, and 3HP completion, defined as the proportion of participants who took at least 11 of 12 doses of 3HP among those who accepted (prespecified as the trial per-protocol analysis). Point estimates of proportions are represented as solid circles with corresponding 97.5% CI error bars. The dotted vertical line at 0.80 represents the prespecified acceptance and completion threshold against which we assessed our coprimary hypothesis. (*) one-sided, 98.75% CI. CI, confidence interval; DOT, directly observed therapy; SAT, self-administered therapy; 3HP, 12 weeks of once-weekly isoniazid and rifapentine.

Fig 3 — Solid circles represent unadjusted PR point estimates, with 97.5% CIs depicted as error bars. Point estimates to the left of the vertical dotted line at a PR of 1.00 favor the first arm listed. CI, confidence interval; DOT, directly observed therapy; PR, prevalence ratio; SAT, self-administered therapy; 3HP, 12 weeks of once-weekly isoniazid and rifapentine.

Of the 1,655 participants included in the primary analysis, 1,651 (99.8%) accepted 3HP. Four participants did not initiate 3HP (3 in the Choice arm and 1 in the DOT arm). There was no strong evidence that 3HP acceptance differed between arms: SAT versus DOT (PR = 1.00; 97.5% CI [0.99, 1.01] p = 0.317), Choice versus DOT (PR 1.00; 97.5% CI [0.99, 1.00] p = 0.317), or Choice versus SAT (PR 0.99; 97.5% CI [0.99, 1.00] p = 0.083; Fig 3). 3HP completion among those who accepted treatment (per-protocol analysis) was high across arms with no evidence of between-arm differences (Fig 2). Results from the as-treated analysis allocating participants in the Choice arm to their selected strategy were similar (PR = 0.98; 97.5% CI [0.95, 1.01] p = 0.077).

Fourteen participants discontinued 3HP due to adverse events: 7 in the SAT arm, 4 in the Choice arm (all 4 chose DOT), and 3 in the DOT arm (S3 Table). Treatment discontinuation due to an adverse event did not differ when comparing SAT versus DOT (risk difference [RD] 0.72%; 97.5% CI [−0.56%, 2.00%] p = 0.206), Choice versus SAT (RD −0.54%; 97.5% CI [−1.88%, 0.81%] p = 0.368), or Choice versus DOT (RD 0.18%; 97.5% CI [−0.89%, 1.26%] p = 0.703) (S4 Table).

Subgroup analyses demonstrated no evidence of differences between any 2 treatment arms (S3 and S4 Figs). Exploratory subgroup analyses found some evidence suggesting that, in the DOT arm, participants with ≥9 years of ART experience had higher acceptance and completion compared to those with <9 years (RD 4.10%; 97.5% CI [−0.19%, 8.39%] p = 0.032). The average per-patient cost to the health system was $139 for DOT, $89 for SAT, and $123 for informed choice. Drugs and transport reimbursement accounted for 76% to 85% of all health system costs (Fig 4).

Fig 4 — Bars represent the average per-patient cost of facilitated 3HP from the health system perspective, according to individual components. “Other health system costs” include costs related to overheads, drug import fees, laboratory, office supplies, and internet charges (a, b). (a) 99DOTS is a technology whereby medications are packaged alongside toll-free phone numbers that are revealed when each dose is unpackaged, enabling patients to make toll-free calls to confirm medication dosing. Clinic staff can remotely access patient adherence data through a web dashboard. IVR reminders, check-in phone calls, and two-way messaging are also core features of the platform that enable real-time identification of patients who miss doses for further follow-up and monitoring of potential side effects. (b) Human resource costs included salaries of pharmacy technicians, lab technicians, clinicians, and entry-level and manager-level research staff. Hourly wages were calculated from government salary scales but adjusted to the project team’s structure and allocated to activities based on direct observation (time and motion studies). DOT, directly observed therapy; IVR, interactive voice response; SAT, self-administered therapy; 3HP, once-weekly isoniazid and rifapentine taken for 3 months.

Fidelity to 3HP treatment and delivery strategy components was high overall and across arms. Overall, 99.4% of expected transport reimbursements were delivered (S5 Table); median time spent at the clinic for 3HP refill or DOT visits was short (median: 10 minutes, IQR: 5 to 20) (S6 Table); >85% of expected IVR check-in calls and appointment reminders were sent to participants (S7 Table); and participants receiving 3HP by SAT confirmed >85% of all expected doses via the 99DOTS platform (S8 Table). Similarly, patient satisfaction with 3HP treatment and delivery strategies was high, with median satisfaction being at the highest level for all questions asked among participants in the Choice arm (S9 and S10 Tables).

Discussion

In this pragmatic type 3 effectiveness-implementation trial involving 1,655 PLHIV completed in Kampala, Uganda, we found high and comparable levels of 3HP acceptance and completion across all delivery strategies tested: facilitated DOT, facilitated SAT, and informed choice. Acceptance and completion rates reached 93.7% overall, surpassing our 80% target in all 3 arms. To the best of our knowledge, these levels are among the highest achieved in the context of routine HIV/TB care in sub-Saharan Africa. Our findings highlight that, with appropriate supports to overcome known barriers [12], very high acceptance and completion of short-course TPT can be attained within routine HIV/AIDS care, regardless of direct observation.

In our trial, completion rates were comparable to those achieved in the WHIP3TB trial conducted in South Africa (90.5%), Ethiopia (95.4%), and Mozambique (82.2%), where trained research staff administered 3HP [10]. In contrast, our completion rate was much higher than the 50% achieved with SAT in the South African iAdhere trial site [9]. However, it is possible in all 3 trials that actual adherence was lower with SAT as pill ingestion was not confirmed. A subgroup analysis of the WHIP3TB trial data, focusing on those who received 3HP facilitated by electronic medication monitoring, found lower treatment completion (83.5%) than the overall completion rate assessed by pill count alone [10]. In our trial, adherence was assessed by both self-report via the 99DOTS platform and pill counts at weeks 6 and 12. We also demonstrate that 3HP was well tolerated, with <1% of participants experiencing adverse events resulting in treatment discontinuation. These findings add to the large evidence base demonstrating the safety/tolerability of 3HP for PLHIV taking efavirenz-based ART [7,19].

Our formative work identified 3 key barriers to 3HP completion: poor understanding of the need for preventive therapy, time and costs of accessing care, long wait times for medications, and difficulty incorporating a new medication into established routines. We addressed these barriers in all delivery strategies with counselling flipbooks designed to facilitate understanding of the importance of TPT for PLHIV, reimbursements covering transportation costs, streamlined clinic visits, and IVR phone call reminders [12]. Survey data reflect that the barriers related to cost and transportation remained a challenge for some participants who were unsuccessful in completing 3HP. However, the overall high level of 3HP acceptance and completion highlights the importance of identifying barriers through formative work and addressing those barriers during implementation.

Equivalent effectiveness and successful implementation of all strategies make cost a crucial consideration. Facilitated SAT is substantially cheaper to the health system than facilitated DOT ($89 versus $139 per patient course), primarily due to fewer clinic visits. The cost difference between DOT and SAT would likely be even higher if people living >25 kilometers of the study clinic were included in the trial, and incorporating participant-level costs (e.g., lost wages, childcare requirements for clinic visits) is likely to only further support facilitated SAT as a cheaper option than facilitated DOT. Shared decision-making in the Choice arm added only marginally to the total cost of 3HP delivery.

Our study’s strengths include strong reliance on implementation science principles and theory-informed frameworks [11,17,20], active involvement of PLHIV and key stakeholders in trial design, and integration of 3HP delivery into routine care, increasing relevance and potential for future scale-up. Person-centeredness was a core aspect of the delivery strategy design, aligning with calls to enhance outcomes while also respecting human dignity [1,21]. Informed choice was introduced as a person-centered approach, showing feasibility and high completion levels when considering people’s lifestyle and preferences.

Despite its strengths, this study also had some limitations. Although we conducted and reported an interim analysis of the primary outcome aggregated across arms [22], the minimal difference in the aggregate proportion accepting and completing 3HP in the interim versus final analysis (0.93 versus 0.94, respectively) and the lack of difference between trial arms suggest that the interim analysis did not have a major impact on final trial results. This was a single center trial that excluded people living further than 25 kilometers from the clinic and those who did not own/have access to a phone. As with any implementation trial, the tested strategies are likely not to be feasible to implement for all individuals in all settings. For example, individuals without cell phones cannot participate in cell phone–based reminder systems; similarly, people who live very far from a clinic are unlikely to be able to participate in DOT. As such, our findings of high acceptance and completion should be interpreted as reflective of what might be achievable among people who could participate in these interventions, not among all PLHIV eligible for TPT in any given clinic. Similarly, some of the delivery strategy components we evaluated (such as transport reimbursements and IVR phone calls) may not be considered feasible in other clinics. However, broader consideration of such costs (which are often lower than the costs of drugs) in health budgets is needed for effective implementation of novel interventions. Lastly, while the barriers to 3HP completion targeted here are likely to be relevant in many settings, further contextual adaptation may be required for facilitated 3HP implementation.

In conclusion, this trial demonstrated high 3HP acceptance and completion among PLHIV in a programmatic setting using theory-informed delivery strategies designed to address known barriers. Policymakers in similar high-burden settings can utilize these findings to inform implementation strategies for short-course TPT (including 3HP) likely to maximize uptake and treatment completion.

Supporting information

S1 Text. Trial inclusion and exclusion criteria.

(DOCX)

pmed.1004356.s001.docx^{(15.1KB, docx)}

S2 Text. Trial statistical analysis plan.

(PDF)

pmed.1004356.s002.pdf^{(622.7KB, pdf)}

S1 Fig. Example of participant 99DOTS-based adherence calendars, including a participant on directly observed therapy (DOT) and a participant on self-administered therapy (SAT).

(DOCX)

pmed.1004356.s003.docx^{(272KB, docx)}

S2 Fig. Self-administered therapy participant pill packs.

(DOCX)

pmed.1004356.s004.docx^{(1.4MB, docx)}

S3 Fig. Subgroup analyses of the primary trial endpoint (acceptance and completion of 3HP).

(DOCX)

pmed.1004356.s005.docx^{(467.9KB, docx)}

S4 Fig. Subgroup analyses comparing 3HP acceptance and completion across trial arms.

(DOCX)

pmed.1004356.s006.docx^{(619.9KB, docx)}

S1 Table. Comparison of choice of delivery strategies across key participant characteristics.

(DOCX)

pmed.1004356.s007.docx^{(19.4KB, docx)}

S2 Table. Reasons for stopping 3HP treatment.

(DOCX)

pmed.1004356.s008.docx^{(18.1KB, docx)}

S3 Table. Adverse events leading to 3HP discontinuation.

(DOCX)

pmed.1004356.s009.docx^{(18.3KB, docx)}

S4 Table. Pairwise comparisons of treatment discontinuation due to an adverse event as unadjusted odds ratios and unadjusted risk differences with corresponding 97.5% confidence intervals (CIs).

(DOCX)

pmed.1004356.s010.docx^{(17.5KB, docx)}

S5 Table. Reimbursement metrics.

(DOCX)

pmed.1004356.s011.docx^{(19.8KB, docx)}

S6 Table. Time spent on 3HP-related activities.

(DOCX)

pmed.1004356.s012.docx^{(18.2KB, docx)}

S7 Table. 99DOTS implementation metrics.

(DOCX)

pmed.1004356.s013.docx^{(21.1KB, docx)}

S8 Table. Confirmation of self-administered doses via 99DOTS.

(DOCX)

pmed.1004356.s014.docx^{(19.2KB, docx)}

S9 Table. Patient Satisfaction Survey Results.

(DOCX)

pmed.1004356.s015.docx^{(20.7KB, docx)}

S10 Table. Responses to Shared Decision-Making Questionnaire.

(DOCX)

pmed.1004356.s016.docx^{(19.2KB, docx)}

S1 CONSORT Checklist. CONSORT 2010 checklist of information to include when reporting a randomized trial.

(DOC)

pmed.1004356.s017.doc^{(219KB, doc)}

S1 Data. Supporting Information Trial Data.

(XLSX)

pmed.1004356.s018.xlsx^{(113.1KB, xlsx)}

Acknowledgments

We are grateful to the staff and clients at the Mulago Immune Suppression Syndrome (ISS) HIV/AIDS clinic for their time and participation in the study.

Abbreviations

ALT: alanine aminotransferase
ART: antiretroviral therapy
AST: aspartate aminotransferase
CI: confidence interval
DOT: directly observed therapy
HCD: human-centered design
IQR: interquartile range
IVR: interactive voice response
PLHIV: people living with HIV
PR: prevalence ratio
RD: risk difference
SAT: self-administered therapy
TB: tuberculosis
TPT: TB preventive treatment
WHO: World Health Organization
3HP: once-weekly isoniazid and rifapentine taken for 3 months

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This study was supported by a grant from the US National Heart, Lung and Blood Institute (https://www.nhlbi.nih.gov/): NIH/NHLBI R01HL144406 (AC). The funder had no role in the study design, data collection and analysis, preparation of the manuscript or decision to publish.

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PLoS Med. doi: 10.1371/journal.pmed.1004356.r001

Decision Letter 0

Katrien G Janin

21 Aug 2023

Dear Dr Cattamanchi,

Thank you for submitting your manuscript entitled "Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV: a randomized trial" for consideration by PLOS Medicine.

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Katrien Janin, PhD

Senior Editor

PLOS Medicine

PLoS Med. doi: 10.1371/journal.pmed.1004356.r002

Decision Letter 1

Katrien G Janin

17 Nov 2023

Dear Dr. Cattamanchi,

Thank you very much for submitting your manuscript "Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV: a randomized trial" (PMEDICINE-D-23-02381R1) for consideration at PLOS Medicine.

Your paper was discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

We will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. We cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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-----------------------------------------------------------

Comments from the academic editor:

It is an excellent paper but in order for this to not be just more data compared to before, further subanalysis would be valuable.

Comments from the editorial team:

We are much in agreement with the academic editor and reviewer #2 that the secondary outcomes should be reported here; particularly given the noted study limitations and that the full results are similar to the interim analysis. We offer major revisions contingent on presentation of secondary outcomes.

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Comments from the reviewers:

Reviewer #1: "Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV: a randomized trial" reports the outcome of a pragmatic three-arm parallel-group randomized trial with about 550 participants in each arm, on acceptance (and adherence) to short-course tuberculosis (TB) prevention treatment, through either of directly observed therapy (DOT), facilitated self-administered therapy (SAT) or an informed choice between DOT and SAT. The main finding was that all three regimens had high acceptance and completion rates (>0.92).

While generally clearly written and extensively documented with implications for TB prevention administration, some issues might be considered:

1. In Line 136, a number of exclusion criteria are stated. In particular, the exclusion for people <40kg might be explained further. What happened to would-be participants weighing less than 40kg?

2. In Line 213, the fidelity rate is defined as the completion of at least 11 of 12 doses of 3HP within 16 weeks of treatment initiation. The definition might be briefly justified.

3. In Line 223, a minimum clinically important difference of 10% is stated. It might be briefly clarified if this was established by custom, empirical justification or prior literature etc.

4. In Line 231, the Supplement number might be stated.

5. In Line 271, it is stated that "...73 participants who initiated 3HP missed six or more doses and were classified as not reaching the primary outcome (unable to complete 11 doses within 16 weeks)". The discrepancy between the actual applied condition (missed six or more doses) and the original definition (complete 11 [of 12 doses, from Line 213]) might be explained.

6. Participant-reported reasons for missing multiple doses might be briefly discussed in the Discussion section, if possible.

7. In Line 347, it is stated that the adherence rate for WHIP3TB might be suggested to be lower than estimated by completion rate, once pill count was considered. Then, it is stated that "...we demonstrate high levels of 3HP completion by SAT facilitated by the 99DOTS adherence technology". It might be clarified as to whether the 99DOTS technology addresses the issue of adherence rate not complementing the completion rate, i.e. how doe 99DOTS solve the problem of pills/doses reported as being taken, but not actually taken?

8. The calculation/data sources (e.g. from surveys?) for the costings reported in Figure 4 might be briefly described.

Reviewer #2: Review for PLoS Medicine

Manuscript Number: PMEDICINE-D-23-02381R1

Full Title: Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV: a randomized trial

October 20, 2023

The authors conducted a randomized controlled implementation science trial to determine the optimal delivery strategies for TB preventive therapy (3HP) in Uganda. The team had two distinct intervention arms, and a third trial arm that allowed people to make an informed choice. Overall, the acceptance and completion rates were high, and there were no differences among the three groups.

The authors have already presented and published an analysis of acceptance and completion rates for this clinical trial cohort (PLoS Med. 2021/12/17 ed. 2021; Dec;18(12):e1003875). The authors should comment on whether and how the presentation/publication of the interim results could have influenced the remainder of the trial.

In addition, the 3HP adoption, implementation, and outcomes measures of TB incidence at one-year are not being reported in this paper. Since the interim analyses showed high levels of acceptability and completion, these secondary outcomes would be helpful to be reported in this paper to help inform programmatic decisions for 3HP delivery programs. Currently, the additional analyses, stratified by study arm, provide limited additional value.

A major limitation of the study is being a single-site clinical study at one urban HIV clinic in Kampala. Given this is an IS study, using results from a single trial site to extrapolate programmatic approaches to the rest of Uganda and/or beyond can be problematic. The rather high treatment completion rates observed in this study also raises concerns that the population (and outcomes) may not be representative of other populations receiving 3HP. The authors could expand on how these results may be relevant (or not) to other settings.

The study did not include a control group that was not receiving adherence support. Therefore, differences above the baseline acceptance and completions rates were not assessed. Thus, the study does not address whether adherence support is still needed with the 3HP regimen. This should be addressed in the Discussion section.

Another limitation was the reliance on pill counting among the SAT group. Since obtaining a pill from a pack may not equate to pill ingestion, this outcome was not as rigorous as other possible measurements. However, given the lack of outcome difference, this issue was unlikely to have been problematic in this cohort.

The study appeared to use a composite outcome of reach and fidelity. The definition for the acceptance component was defined in Figure 2, but should be moved to the Methods section. Furthermore, reporting an outcome of acceptance is not particularly helpful for an RCT with informed consent (as evidenced in Figure 2). This outcome could be removed from Figure 2, Fig 3, and elsewhere.

Similarly, The 'informed choice' column can be removed from Figure 4, since this is a weighted average of participants who joined the 2 interventions. While this may be a representative cost for this study arm, it does not appear to represent raw data collected within the choice intervention.

Overall, there was a high rate of exclusion for people not residing in the local area. This likely had an impact on the high completion rates, and also limits generalizability of study findings. The impact of this exclusion criteria and the impact of interpretation should be discussed.

Reviewer #3: I commend the authors on conducting a well-designed, thoughtful and clinically relevant prospective 3-arm type 3 hybrid effectiveness-implementation study into three delivery strategies (DOT, self administered therapy or informed choice) for 3HP treatment of latent TB integrated into the workflow of a single large outpatient clinic serving persons with HIV in Kampala, Uganda. I agree with the authors that making shorter effective TB preventative therapy (latent TB) regimens such as 3HP more widely available among persons with HIV in high burden settings is a key component of the END TB strategy, and as noted by the authors in the introduction and discussion sections previous studies including iAdhere and WHIP3TB have found variable rates of treatment completion with regard to self-administered 3HP in other clinical settings in Africa. Among the 1655 participants in the primary analysis, those in all 3 arms achieved very high rates of acceptance and completion of 3HP treatment. The inclusion criteria and exclusion criteria are clearly laid out. Persons with HIV who started ART within the preceding 3 months were excluded and the authors should specify why this cutoff was used- I am slightly unclear as to whether the concern was for drug interactions between rifapentine and ART or for IRIS/unmasking of opportunistic infections as potential confounders of study outcomes. The exclusion of otherwise eligible participants who either did not have a cellphone to receive SMS reminders/automated calls and the exclusion of participants living >25km from the clinic do limit the generalizability of the findings and procedures used with regard to other settings in sub-Saharan Africa, where patients may need to travel long distances to receive care and where availability of cellphone coverage can vary, especially in rural settings. While the authors hint at this in the comments about generalizability to rural settings in the discussion section, I think these are important considerations that would strengthen the discussion. Additionally, I note from the protocol that only those participants who could consent in Luganda or English were eligible, and that another limitation in terms of implementing the phone-based reminder strategies used in this research study more broadly in other resource limited settings may be the need for materials in multiple languages and strategies to mitigate barriers based on literacy. This is where I feel that the single center approach used is something of a limitation, as implied by the authors in the penultimate paragraph of the discussion. The authors do acknowledge that reimbursement of travel and some of the other strategies to mitigate barriers to treatment completion may not be feasible in other settings and that the the barriers may differ in different settings. Overall, while this study failed to show that informed choice performed significantly better than DOT or self-administered therapy for 3HP in this setting, the authors clearly demonstrate in their results that self-administered therapy with 3HP is associated with high rates of acceptance and completion in a routine HIV clinic setting in sub-Saharan Africa. I look forward to the promised additional analyses of secondary endpoints, such as TB incidence at 1 year and cost-effectiveness analysis as mentioned in the 'Outcomes' paragraph of the methods section.

Reviewer #4: I appreciate the opportunity to review this manuscript. The assessment of delivery strategies to improve the acceptance and completion of preventive therapy in people living with HIV is an incredibly important topic being studied in a high-risk population. I praise the use of human centered design methods and person-centered care principles for the optimization of delivery of 3HP. The high acceptance and completion of 3HP is incredibly promising, especially because of the authors' work done locally to integrate these delivery strategies into routine care and the potential for scale-up. I applaud the authors for an incredibly well-written manuscript that is clear to follow and thorough in its description. All tables and figures are clear and concise. While I fully support this manuscript for publication, I have a few minor suggestions for the final version:

1) Did the authors assess completion results separately for individuals who received loose pills early on in the trial vs fixed-dose combination pills later in the trial? Do they anticipate any difference in acceptance or completion based on this?

2) Did the authors consider also conducting analysis for all those who were assigned a strategy (DOT or SAT) compared to all those who were provided a choice (despite which strategy they chose) to assess whether just having a choice in their healthcare management improved their acceptance or completion?

3) The article might benefit from a few more details in the methods section about how costs were collected and calculated.

4) Some information in the discussion re: formative work identifying barriers that were incorporated into the delivery strategies would be beneficial to describe in the context of the description of the strategies in the methods section.

Reviewer #5: I considered the work of Prof. Adithya Cattamanchi and colleagues to be an extension of their published interim analysis, and it is a well-documented study. I would like the following explanations.

1. Lines 136-142: The paragraph's exclusion criteria seem repetitive because Supplement 1 already mentions them.

2. Was the relationship between education level and the informed Choice 3HP preventative treatment examined by the author?

3. All three treatment arms have similar median and range ages. How could that be?

4. Why were there more female participants in all three arms of the study, despite the fact that those who were pregnant, breastfeeding a baby, or planning to get pregnant within the next 120 days were not eligible?

5. What is prior Tuberculosis? Patients with active tuberculosis, suspicion of active tuberculosis, and those who previously completed treatment for tuberculosis were not eligible for the study.

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

[LINK]

PLoS Med. 2024 Feb 20;21(2):e1004356. doi: 10.1371/journal.pmed.1004356.r003

Author response to Decision Letter 1

13 Dec 2023

Attachment

Submitted filename: Response to Reviewers.docx

pmed.1004356.s019.docx^{(65.9KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004356.r004

Decision Letter 2

Katrien G Janin

19 Jan 2024

Dear Dr. Cattamanchi,

Thank you very much for re-submitting your manuscript "Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: a single-center randomized trial" (PMEDICINE-D-23-02381R2) for review by PLOS Medicine.

I appreciate your detailed response to the editors' and reviewers' comments. I have discussed the paper with my colleagues and the academic editor, and it has also been seen again by four of the original reviewers. The changes made to the paper were satisfactory to the reviewers. As such, we intend to accept the paper for publication, pending your attention to the editorial comments below in a further revision. When submitting your revised paper, please once again include a detailed point-by-point response to the editorial comments.

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]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

We ask that you submit your revision within 1 week (Jan 26 2024). However, if this deadline is not feasible, please contact me by email, and we can discuss a suitable alternative.

Please do not hesitate to contact me directly with any questions (aschaefer@plos.org). If you reply directly to this message, please be sure to 'Reply All' so your message comes directly to my inbox.

We look forward to receiving the revised manuscript.

Sincerely,

Alexandra Schaefer, PhD

On behalf of:

Katrien Janin, PhD

Associate Editor

PLOS Medicine

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Requests from Editors:

ABSTRACT

1) Abstract Background: Please provide the study question/hypothesis as the final sentence of the background section.

2) Please remove the trial registration details from the Methods and Findings section and add it at the end of the abstract as a separate information.

3) In the last sentence of the Abstract Methods and Findings section, please clearly describe the main limitation(s) of the study's methodology. Editorial suggestion: The main limitation of the study is that it was conducted in a single center, and multicenter studies are now needed to confirm the feasibility and and generalizability of facilitated 3HP delivery strategies in other settings.

AUTHOR SUMMARY

1) Under ‘Why Was This Study Done?’, we feel the second bullet point describes differences to two previous implementation trials without clearly stating the reason for conducting the current study. Please revise. Editorial suggestion: Two previous implementation trials have evaluated the delivery of 12 weeks of isoniazid and rifapentine (3HP) through self-administered therapy (SAT) in high-burden settings and found variable treatment completion rates, in both studies, 3HP dosing and treatment supervision were provided by research staff rather than routine health workers.

2) Please revise the bullet points under ‘What Did the Researchers Do and Find?’. We feel that a bullet point describing treatment options is currently missing and that the interpretation of these findings should be limited to question 3 (What Do These Findings Mean?). Editorial suggestion:

• In a pragmatic trial, 1,655 people living with HIV (PLHIV) at a high-volume clinic in Kampala, Uganda, received 3HP either by facilitated directly observed therapy (DOT) involving a pharmacy technician, facilitated self-administered therapy (SAT), or informed choice between facilitated DOT and facilitated SAT using a shared decision-making aid.

• We found high levels of 3HP completion in the context of routine HIV/AIDS care.

• The high completion rates were independent of therapy delivery strategy.

INTRODUCTION

1) ll.134-135: Please provide reference for the sentence starting “Scaling up TPT is crucial...”.

2) l.143: Please exchange ‘Both’ with ‘Two’.

METHODS AND RESULTS

1) ll.209-226: We feel that the detailed descriptions of facilitated directly observed therapy (DOT), facilitated self-administered therapy, and informed choice delivery strategies provided in Supplement 2 should be included in the main manuscript. Please revise accordingly and remove Supplement 2.

2) ll.240-250: In the Methods section under “Outcomes”, we ask that you include a complete list of secondary outcomes (it is not necessary to include all sub-bullet points as listed in the published protocol), followed by a statement about which of them are reported in this paper. Please also mention that data on efficacy endpoints are still being collected.

3) l.282: The terms gender and sex are not interchangeable (as discussed in https://www.who.int/health-topics/gender); please use the appropriate term. We suggest using the word 'female' here.

4) l.286: Given that Supplement 4 contains 8 tables, we suggest specifying the reference (here: Table 1 in Supplement 4). Please revise throughout the main manuscript.

5) l.313: “one who died in a motor vehicle accident.” - We suggest that this statement be reworded to read "one who died for reasons unrelated to the trial". Since the study was conducted in a single center and at a specific time, we are concerned that this may expose the deceased individual.

6) Per CONSORT, please present adverse events in a table and discuss whether or not adverse events are thought to be related to treatment.

DISCUSSION

1) l.424: “Informed choice was introduced as a novel, person-centered…” – please remove the word ‘novel’.

2) l.446: Please remove the word “extremely”.

FIGURES

1) Figure 1: Please define '3HP'. Please note that it is not necessary to define abbreviations within the figure and additionally list these abbreviations below the figure, either one is sufficient.

2) Figure 1: In the boxes directly above the numbers analyzed: In the SAT group, it is not necessary to indicate that "0 never initiated therapy", please remove.

3) Figure 4: We suggest adding footnotes detailing what the 99DOTS platform is and what human resources includes.

REFERENCES

When specifying the date of access, please write “accessed” instead of “cited”.

SUPPLEMENTARY MATERIAL

1) Please be sure to define 3HP where applicable.

2) Please be sure to define what the strategy “Choice” encompasses where applicable.

3) Supplement Figure 1: Please also define the meaning of the yellow boxes.

4) Supplement Figure 3: Please change ‘women’ and ‘men’ to ‘female’ and ‘male’.

5) Supplement Figure 4: Please change ‘women’ and ‘men’ to ‘female’ and ‘male’. Please mention in the figure description that the colours indicate the pre-specified subgroups (red = sex, blue = age, purple = time on ART, green = prior TB status).

SOCIAL MEDIA

To help us extend the reach of your research, please provide any X (formerly known as Twitter) handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.

Comments from Reviewers:

Reviewer #1: We thank the authors for addressing our previous concerns.

Reviewer #2: The authors have been mostly responsive to the prior comments, and the manuscript is suitable for publication. However, given the dis-aggregated adherence measures were similar across 3 study arms, and the aggregated results have been previously published, this manuscript adds little value to the prior publication. The addition of the secondary outcomes was helpful, but also did not add much value to this manuscript.

Reviewer #3: The revisions and author responses have addressed all of my previous comments and concerns about this manuscript. The revised version is clearly written and improved by the incorporation of suggestions made by my fellow reviewers. In the Methods and Findings section of the abstract, consider the following very minor change for improved readability 'facilitated SAT using a shared decision-making aid' would perhaps be clearer as 'facilitated SAT using a shared decision-making aid (Choice)' to be consistent with the designation used later in the manuscript for the third group of participants.

Reviewer #4: I appreciate the thoughtful and comprehensive response to the reviewers' comments. All pending queries have been resolved and I support this manuscript for publication.

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

[LINK]

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General Editorial Requests

1) We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

2) Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

3) Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

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PLoS Med. 2024 Feb 20;21(2):e1004356. doi: 10.1371/journal.pmed.1004356.r005

Author response to Decision Letter 2

1 Feb 2024

Attachment

Submitted filename: Response to Reviewers_2nd review.docx

pmed.1004356.s020.docx^{(31.3KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004356.r006

Decision Letter 3

Katrien G Janin

2 Feb 2024

Dear Dr Cattamanchi,

On behalf of my colleagues and the Academic Editor, I am pleased to inform you that we have agreed to publish your manuscript "Comparison of three optimized delivery strategies for completion of Isoniazid-Rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: a single-center randomized trial" (PMEDICINE-D-23-02381R3) in PLOS Medicine.

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Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Katrien G. Janin, PhD

Senior Editor

PLOS Medicine

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Text. Trial inclusion and exclusion criteria.

(DOCX)

pmed.1004356.s001.docx^{(15.1KB, docx)}

S2 Text. Trial statistical analysis plan.

(PDF)

pmed.1004356.s002.pdf^{(622.7KB, pdf)}

S1 Fig. Example of participant 99DOTS-based adherence calendars, including a participant on directly observed therapy (DOT) and a participant on self-administered therapy (SAT).

(DOCX)

pmed.1004356.s003.docx^{(272KB, docx)}

S2 Fig. Self-administered therapy participant pill packs.

(DOCX)

pmed.1004356.s004.docx^{(1.4MB, docx)}

S3 Fig. Subgroup analyses of the primary trial endpoint (acceptance and completion of 3HP).

(DOCX)

pmed.1004356.s005.docx^{(467.9KB, docx)}

S4 Fig. Subgroup analyses comparing 3HP acceptance and completion across trial arms.

(DOCX)

pmed.1004356.s006.docx^{(619.9KB, docx)}

S1 Table. Comparison of choice of delivery strategies across key participant characteristics.

(DOCX)

pmed.1004356.s007.docx^{(19.4KB, docx)}

S2 Table. Reasons for stopping 3HP treatment.

(DOCX)

pmed.1004356.s008.docx^{(18.1KB, docx)}

S3 Table. Adverse events leading to 3HP discontinuation.

(DOCX)

pmed.1004356.s009.docx^{(18.3KB, docx)}

S4 Table. Pairwise comparisons of treatment discontinuation due to an adverse event as unadjusted odds ratios and unadjusted risk differences with corresponding 97.5% confidence intervals (CIs).

(DOCX)

pmed.1004356.s010.docx^{(17.5KB, docx)}

S5 Table. Reimbursement metrics.

(DOCX)

pmed.1004356.s011.docx^{(19.8KB, docx)}

S6 Table. Time spent on 3HP-related activities.

(DOCX)

pmed.1004356.s012.docx^{(18.2KB, docx)}

S7 Table. 99DOTS implementation metrics.

(DOCX)

pmed.1004356.s013.docx^{(21.1KB, docx)}

S8 Table. Confirmation of self-administered doses via 99DOTS.

(DOCX)

pmed.1004356.s014.docx^{(19.2KB, docx)}

S9 Table. Patient Satisfaction Survey Results.

(DOCX)

pmed.1004356.s015.docx^{(20.7KB, docx)}

S10 Table. Responses to Shared Decision-Making Questionnaire.

(DOCX)

pmed.1004356.s016.docx^{(19.2KB, docx)}

S1 CONSORT Checklist. CONSORT 2010 checklist of information to include when reporting a randomized trial.

(DOC)

pmed.1004356.s017.doc^{(219KB, doc)}

S1 Data. Supporting Information Trial Data.

(XLSX)

pmed.1004356.s018.xlsx^{(113.1KB, xlsx)}

Attachment

Submitted filename: Response to Reviewers.docx

pmed.1004356.s019.docx^{(65.9KB, docx)}

Attachment

Submitted filename: Response to Reviewers_2nd review.docx

pmed.1004356.s020.docx^{(31.3KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Comparison of 3 optimized delivery strategies for completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV in Uganda: A single-center randomized trial

Fred C Semitala

Jillian L Kadota

Allan Musinguzi

Fred Welishe

Anne Nakitende

Lydia Akello

Lynn Kunihira Tinka

Jane Nakimuli

Joan Ritar Kasidi

Opira Bishop

Suzan Nakasendwa

Yeonsoo Baik

Devika Patel

Amanda Sammann

Payam Nahid

Robert Belknap

Moses R Kamya

Margaret A Handley

Patrick PJ Phillips

Anne Katahoire

Christopher A Berger

Noah Kiwanuka

Achilles Katamba

David W Dowdy

Adithya Cattamanchi

Roles

Abstract

Background

Methods and findings

Conclusions

Trial Registration

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Ethics statement

Study design and participants

Randomization and masking

Fig 1. Trial profile.

Interventions

Facilitated DOT

Facilitated SAT

Informed choice

Data collection

Outcomes

Statistical analysis

Results

Table 1. Participant baseline characteristics, by study arm (N = 1,655)a.

Fig 2. 3HP acceptance and completion, by study arm.

Fig 3. Comparison of study outcomes across arms (N = 1,655).

Fig 4. Per-patient cost of facilitated 3HP delivery from the health system perspective.

Discussion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Katrien G Janin

Roles

Decision Letter 1

Katrien G Janin

Roles

Author response to Decision Letter 1

Decision Letter 2

Katrien G Janin

Roles

Author response to Decision Letter 2

Decision Letter 3

Katrien G Janin

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

Table 1. Participant baseline characteristics, by study arm (N = 1,655)^a.