CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

improved gonadal status, consistent with improved spermatogenesis. Body weight increased, indicating improved health status. Sputum cultures were negative in all participants from Week 8 onwards. Of 26 enrolled participants, 2 discontinued treatment due to elevated liver enzymes, one due to pyrazinamide resistance and one withdrew consent. Two participants experienced serious adverse events (infectious exacerbation of bronchiectasis and increased liver enzymes). Conclusion: This is the first study designed to investigate severe testicular toxicity in adult males with DR-TB. Results show that pretomanid, as part of the BPaMZ regimen, does not appear to have negative effects on reproductive function in adult males with DR-TB.

formation. Here we describe the PK of INH, INA, AcINH, AcHz, and Hz in AP and PP WWH receiving IPT. Methods: Samples and data from intensive PK assessments among WWH enrolled in P1078 were included in the analysis. WWH received INH 300 mg once daily for at least 2 weeks prior to the intensive PK assessment. Samples were collected at 0, 1, 2, 4, 6, 8 and 12 h post-dose. Intensive PK during AP occurred ≥28 weeks of gestation and 16 (±2) weeks PP. INH, INA, AcINH, AcHz, and Hz were quantified using a validated LC-MS/MS method (lower limit of quantification 10 ng/mL for all analytes). PK data were analyzed using noncompartmental methods. Data were summarized descriptively by pregnancy stage and NAT2 acetylation status (fast, intermediate, slow). Linear mixed models were used to compare percent differences (95% confidence intervals [CI]) between AP vs. PP for each analyte. Results: Data from 31 WWH were analyzed (10 AP and PP, 4 AP only, 17 PP only). The median (range) gestational age at entry was 26 (14-34) weeks. Maternal median (range) age was 29 (18-41) years with 81% Black and 19% Asian. Observed AcINH exposures were higher among intermediate and fast acetylators, whereas INH, INA, and AcHz exposures were higher in intermediate and/or slow acetylators (Table). INA and AcHz were lower AP versus PP after controlling for NAT2 status. Hz was quantifiable in 5/14 AP and 23/27 PP WWH, with numerically higher AUCs observed PP. Conclusion: These data demonstrate relationships between NAT2 and the formation of INH metabolites in pregnant and postpartum WWH. INA and AcHz AUCs were higher and Hz was detectable in more women during PP. Analyses to examine the influence of pregnancy and other factors affecting INH metabolite PK in the overall study population and potential associations with hepatotoxicity in P1078 are ongoing. Testicular Safety of a Pretomanid Regimen (BPaMZ) in Men With Pulmonary Drug-Resistant Tuberculosis Pauline Howell 1 , Francesca Conradie 2 , William Brumskine 3 , Lali Mikiashvili 4 , Joanna Moreira 5 , Antonio Lombardi 5 , Alda Holsta 5 , Matthew Betteridge 5 , Paul Bruinenberg 5 , Maria Beumont 5 , Eugene Sun 5 1 Clinical HIV Research Unit, Johannesburg, South Africa, 2 Isango Lethemba - TB Research Unit, Gqeberha, South Africa, 3 The Aurum Institute, Johannesburg, South Africa, 4 National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia, 5 Global Alliance for TB Drug Development, New York, NY, USA Background: Testicular toxicity was observed in rodents exposed to high doses of pretomanid. Pretomanid is approved for use in treatment regimens for drug resistant tuberculosis (DR-TB). This study evaluated the testicular safety of 26 weeks of pretomanid in adult males with DR-TB as part of a BPaMZ (bedaquiline, pretomanid, moxifloxacin, pyrazinamide) regimen. Methods: Twenty-six men with DR-TB were enrolled at 4 sites in South Africa and Georgia. They received BPaMZ at recommended doses for 26 weeks, with a 52-week safety follow-up. The primary outcome was the change from baseline in total sperm count at Week 26. Secondary outcomes included change from baseline in total sperm count at Week 12 and 44; change from baseline over time in sperm concentration, sperm volume, and male reproductive hormones (testosterone, inhibin B, FSH, LH). Results: Of 26 men enrolled, 22 completed treatment and were assessed for study endpoints. Among completers, mean age was 36 years, 68% were Black and 36% living with HIV. At the Week 26 timepoint (primary outcome), mean total sperm count increased from baseline by 20.0x106 sperm/ejaculate. Mean sperm concentration increased from baseline at Week 26 by 25.8x106 sperm/mL. For both total sperm count and sperm concentration, 13/22 (59%) participants had a >50% increase by Week 26. At Week 26, 2 participants had a >50% decrease in total sperm count, maybe due to low semen volume, while none had a >50% decrease in sperm concentration. There was large variability in sperm parameters among participants. Mean semen volume was unchanged at both Week 12 and 26. Reproductive hormone changes showed

873

Cardiac Involvement in Tuberculosis Patients at the Start and End of Treatment in Southern Africa Daryoush Samim 1 , Guy Muula 2 , Douglas Chibomba 3 , Sihle Xulu 4 , Nicolas Banholzer 5 , Stefano De Marchi 1 , Gunar Günther 1 , Denise Evans 4 , Carolyn Bolton 6 , Matthias Egger 5 , Thomas Pilgrim 1 , Lukas Fenner 5 , for IeDEA Southern Africa (IeDEA-SA) 1 University Hospital of Bern, Bern, Switzerland, 2 Centre for Infectious Disease Research in Zambia, Lusaka, Zambia, 3 University Teaching Hospital, Lusaka, Zambia, 4 Health Economics and Epidemiology Research Office, Johannesburg, South Africa, 5 Institute of Social and Preventive Medicine, Bern, Switzerland, 6 Center for Infectious Disease Research in Zambia, Lusaka, Zambia Background: Tuberculosis (TB) primarily affects the lungs but can also involve cardiovascular structures such as the pericardium. Little is known about the type, frequency, and clinical significance of cardiovascular involvement in people with TB. We established two cohorts in Zambia and South Africa to measure pulmonary and cardiovascular complications in HIV-positive and HIV negative TB patients before and after TB treatment. Methods: As part of the ongoing TB cohort, we consecutively recruited clinically or microbiologically confirmed TB patients (>15 years old) between October 2022 and July 2023 in Lusaka/Zambia and Johannesburg/South Africa. Clinical and laboratory data were collected electronically from all participants. We performed standardized transthoracic echocardiography at the start (baseline) and at the end of TB treatment (6-month follow-up). We estimated associations of pericardial changes with baseline characteristics using linear regression models. Results: We included 240 TB patients; 50 had follow-up images. The median age was 34 years (Interquartile range: 28-42 years); 187 (78%) were men, and 92 (38%) were HIV-positive. At baseline, most frequent echocardiographic abnormalities were pericardial effusion (PE; 116 persons, 48%) and pericardial thickening (PT; 82, 34%), followed by left atrial (LA) dilatation (39/225, 17%) and pericardial calcifications (7, 3%); 4/49 (8%) had diastolic dysfunction. Signs of constriction (SoC) were observed in 94/201 (47%) patients and a definitive diagnosis of constriction was made in 15/70 (21%) patients at baseline. Abnormal LV geometry was found in 111/228 (49%) patients, most commonly concentric remodeling (97, 87%). LV dilatation was seen in 2/225 (1%) patients and RV dilation in 14/208 (7%). Left ventricular (LV) systolic function was preserved in almost all patients (235/237, 99%), and right ventricular (RV) systolic dysfunction was observed in 11/224 (5%) patients. PT tended to be negatively associated with HIV infection, PE with younger age (Figure A). In 50 patients with follow-up imaging, pericardial changes tended to improve during TB treatment (Figure B). Conclusion: Cardiac involvement of TB patients at the time of treatment start were relatively frequent, particularly signs of constrictive pericarditis. Pericardial thickening tended to be less frequent in TB patients with HIV. Outcomes tended to improve during treatment, but long-term outcomes

Poster Abstracts

872

CROI 2024 270