CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: Participants initiating 3HP through a randomized trial had higher CD4 counts, were more likely to complete TPT and had lower TB incidence than those who received TPT through routine clinic procedures. Standardized protocols to assess TPT eligibility, monitor AEs and ensure completion will be critical to optimizing the impact of TPT among people initiating ART in high TB/ HIV burden settings.

3HP eligibility using a standardized questionnaire and liver enzyme testing; those eligible initiated self-administered 3HP two weeks after ART initiation. HIV viral load (VL) was measured as part of routine care at 6 and 12 months. We evaluated 3HP discontinuation due to drug toxicity among participants receiving 3HP+TLD, and compared viral suppression (VL≤50 copies/mL) among adults who initiated 3HP+TLD vs TLD alone using chi-square tests and log binomial regression. Results: From November 2020 to January 2023, 1,379 participants without TB initiated TLD, including 539 (39.1%) who initiated 3HP (163 participants receiving 3HP+TLD were previously reported). Those who initiated 3HP+TLD were more likely to be male (35% vs 31%, p=0.06) and had higher pre-ART CD4 counts (median 296 vs 238 cells/μL, p<0.01) than those who initiated TLD alone. Overall, 509 of 539 (94%) participants completed 3HP; reasons for discontinuation included adverse events (n=2), TB diagnosis (n=3), pregnancy (n=3), and self-discontinuation (n=22). Of 974 (71%) participants with 6-month VL results and 536 (39%) participants with 12-month VL results, there was no difference in viral suppression (VL≤50 copies/mL) between those who received 3HP+TLD vs TLD alone (6-months: 72.7% vs 72.8%; adjusted risk ratio [aRR] 1.00, 95%CI 0.93-1.08; 12-months: 76.3% vs 77.3%; aRR 0.97, 95%CI 0.89-1.07). Conclusion: Co-administration of 3HP+TLD was well-tolerated, with high completion. Now with data from 1,379 participants, and contrary to our interim findings, there was no difference in viral suppression between those receiving TLD+3HP versus TLD alone. Outcomes of Adults With HIV Receiving TB Preventive Therapy in Kampala, Uganda Elise Dressel 1 , Fred C. Semitala 2 , Shafic Makumbi 3 , Bishop Opira 3 , Patrick P. Phillips 4 , David Dowdy 5 , Lelia H. Chaisson 1 , Christina Yoon 4 1 University of Illinois at Chicago, Chicago, IL, USA, 2 Makerere University College of Health Sciences, Kampala, Uganda, 3 Infectious Diseases Research Collaboration, Kampala, Uganda, 4 University of California San Francisco, San Francisco, CA, USA, 5 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: After decades of underuse, tuberculosis preventive therapy (TPT) underwent rapid scale-up in Uganda in 2020 as part of a national campaign. This campaign overlapped with a pragmatic trial comparing the impact of TB screening strategies on TPT uptake among antiretroviral therapy (ART)-naïve adults that also included standardized protocols for assessing TPT eligibility and TPT-specific follow-up. We compared clinical outcomes among trial participants who received study- vs clinic-initiated TPT. Methods: In an ongoing randomized controlled trial (NCT04557176), participants who screened negative for TB were assessed for 3HP (3-months weekly isoniazid+rifapentine) eligibility using a standardized questionnaire and liver enzyme testing. Eligible participants started self-administered 3HP two weeks after ART initiation; participants were assessed monthly for adverse events (AEs) using standardized checklists and adherence by pill count. Those ineligible for study-initiated 3HP were reassessed through routine care after three months and were offered clinic-initiated, self-administered TPT (isoniazid or 3HP) based on clinical assessment. Completion of clinic-initiated TPT was assessed by recall at the end of treatment. We compared personal characteristics, TPT completion and TB incidence among participants initiating study- vs clinic-initiated TPT. Results: Of 1,719 total participants, 541 (31%) received study-initiated 3HP and 235 (14%) received clinic-initiated TPT (94% isoniazid, 6% 3HP). Median follow up was 584 days (IQR 422-727). Study-initiated participants were younger (median 29 vs 32 years, p=0.01), more often female (65% vs 59%, p<0.01), and had higher pre-ART CD4 counts (median 295 vs 138 cells/µL, p<0.01) than clinic-initiated participants. Permanent TPT discontinuations due to suspected AEs were uncommon for both groups (≤1.5%), but completion was higher for study- than clinic-initiated TPT (94.5% vs 76.6%, p<0.01; Table). TB incidence was lower among participants initiating TPT through the study than through the clinic (0.2% vs 2.1%, p=0.01).

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Long-Acting Injectable Rifapentine With Activity in a Mouse Model of Tuberculosis Preventive Therapy Henry Pertinez 1 , Nicole C. Ammerman 2 , Si Yang Li 2 , Jonathan Massam 1 , James J. Hobson 1 , Alison C. Savage 1 , Joanne Sharp 1 , Joanne Herriott 1 , Edyta Kijak 1 , Eduardo Gallardo-Toledo 1 , Megan Neary 1 , Steve Rannard 1 , Susan Swindells 3 , Andrew Owen 1 , Eric Nuermberger 2 1 University of Liverpool, Liverpool, United Kingdom, 2 The Johns Hopkins University, Baltimore, MD, USA, 3 University of Nebraska Medical Center, Omaha, NE, USA Background: Use of long-acting injectables (LAIs) has the potential to simplify tuberculosis preventive therapy (TPT) addressing issues such as pill burden and adherence. Rifapentine (RPT) is a key component of shorter TPT regimens and has physicochemical and pharmacokinetic (PK) properties amenable to LAI formulation. The aim of this work was to characterize preclinical performance of a new RPT single phase spray dried nanosuspension LAI for use in TPT. Methods: Single intramuscular dose PK profiles were first characterized in mice and rats. Based on mouse PK, 8 RPT-LAI regimens were used to evaluate bactericidal activity in a validated mouse model of TPT. RPT (93.75, 187.5, and 375 mg/kg) was administered via 1, 2 or 4 injections over 4 weeks in expectation of clearing a 0.6 μg/mL plasma target. With 3 control groups [untreated negative control; positive control daily oral isoniazid and RPT (1HP); 4 weeks of oral RPT], a total of 186 adult female BALB/c mice were used. Lung bacterial colony-forming units (CFU) counts and plasma RPT exposures were measured 2-8 weeks after the start of treatment. Group mean CFU counts were analyzed using 1-way ANOVA and plasma exposure with compartmental PK analysis. Results: LAI-RPT demonstrated dose-linear PK for single injection doses of 187.5 and 375 mg/kg (AUC0-14d 6629 and 13071 μg·h/mL, respectively) in mice, with PK disposition parameter estimates in keeping with reported mouse RPT values and a release-dependent, "flip-flop" terminal phase (Fig.1A). As for other successful LAI which demonstrate longer half-lives in larger species, longer exposure durations were observed in rats. All RPT-LAI regimens had bactericidal activity in mice, which was dose-dependent and greatest when divided into 4 weekly injections. Several regimens had bactericidal activity equal to or greater than the 1HP control regimen: 375 mg/kg x 1, 93.75 mg/kg x 2, 187.5 mg/kg x 2, 93.75 mg/kg x 4, and 46.9 mg/kg x 4 injections (Fig.1B). PK after 2nd, 3rd or 4th dose in multiple injection regimens were inconsistent with single injection PK, with plasma exposures falling below 0.6 μg/mL target by 1 week post dose. Conclusion: These data provide proof-of-concept for RPT-LAI to achieve efficacy comparable to 1HP in a validated mouse TPT model. Cross-species PK data suggest that efficacious RPT exposures should be achievable in humans. Further work to characterize the impact of repeat dosing on PK and conduct GLP toxicology studies to support first in human evaluation are underway.

Poster Abstracts

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