CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

with increased frequency of total monocytes compared to LTBI (5.1% vs 3.7%; p=0.013), but not when compared to PWH without Mtb infection. HLA-DR density on all monocyte subsets was higher in PWH with LTBI or prior TB compared to PWH without Mtb infection (Table). In multivariable regression, a higher frequency of inflammatory monocytes remained associated with HIV infection after adjusting for TB status, age, sex, cholesterol, and diabetes mellitus (log-%, b=0.37; p=0.019). Among PWH, a higher density of HLA-DR on monocytes remained associated with LTBI or prior TB in adjusted modeling (log-MFI; b=1.17; p<0.001). Conclusion: Inflammatory monocytes are expanded in HIV infection. LTBI and prior active TB were associated with increased HLA-DR expression on all monocyte subsets in PWH, which indicates increased immune activation in the setting of Mtb and HIV coinfection.

E. Dorman 5 , Elin M. Svensson 6 , Andreas H. Diacon 1 , Kelly E. Dooley 4 , for the COMRADE Study Team 1 TASK Applied Science, Cape Town, South Africa, 2 Stellenbosch University, Cape Town, South Africa, 3 BJGMC Clinical Trials Unit, Pune, India, 4 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 5 Medical University of South Carolina, Charleston, SC, USA, 6 Radboud University Medical Center, Nijmegen, Netherlands Background: A dose finding study was conducted to measure the early bactericidal activity (EBA) of meropenem and amoxicillin/clavulanate, with or without rifampicin, in patients with pulmonary tuberculosis. Methods: In this Phase 2A RCT, patients with sputum smear-positive pulmonary TB were randomized to receive 14 days of: Meropenem 2g TID plus Rifampicin 20 mg/kg (Arm C); Meropenem 2g TID (Arm D); Meropenem 1g TID (Arm E) or Meropenem 3g QD (Arm F). All received Amoxicillin/Clavulanate. Overnight sputumwas collected on days 0, 1, 2, 3, 4, 6, 8, 10, 12, 14. The mean daily fall in log 10 colony forming units (CFU) of M. tuberculosis per mL of sputum over 14 days of treatment (EBA0-14CFU) was calculated. Intensive PK sampling over 8h was performed on Day 13. PK data were analyzed in R and WinNonlin. EBA0-14 CFU were calculated as [baseline log 10 CFU/mL – log 10 CFU/mL at day 14]/14. Results: Sixty patients were recruited in Cape Town, South Africa. Mean (range) age was 36.8 years (19.9-62.7), 75%were male, and 23.3%were HIV- positive. Mean AUC0-24 for regimens C, D, E, and F, were 573, 555, 289, and 315 h*mg/L, respectively; C max were 133, 134, 68.1, and 179 mg/L, respectively. Over 14 days, mean (95% CI) EBA0-14CFU were 0.11 (0.03-0.18), 0.11 (0.06-0.17), 0.05 (0.01, 0.09), and 0.03 (-0.01, 0.08), in Arms C, D, E, and F, respectively (Figure). Over the first 2 days of treatment, mean EBA0-2CFU were 0.39; 0.11; 0.14; and 0.02, in regimens C, D, E, and F, respectively. Conclusion: Meropenem exhibits linear dose-dependent PK, and rifampicin does not impact its exposures. Addition of Rifampicin to Meropenem and Amoxicillin/Clavulanate increased early EBA (EBA0-2) but did not significantly increase 14-day EBA. 14-day EBA was significantly higher with Meropenem doses of 2g thrice-daily (total daily dose of 6g) than with total daily doses of 3g. With total daily doses of 3g, given once-daily or in divided doses, 14-day EBA was negligible, and similar. The activity of Meropenem against drug-resistant strains remains to be explored.

731 INTRAVENOUS BCG VACCINATION IN SIV+ MACAQUES CONFERS HIGH- LEVEL PROTECTION AGAINST TB Erica C. Larson 1 , Mark A. Rodgers 1 , Amy Ellis 2 , Cassaundra A. Ameel 1 , Janelle Gleim 1 , Abigail K. Gubernat 1 , Alexis Balgeman 2 , Ryan Moriarty 2 , Pauline Maiello 1 , Patricia A. Darrah 3 , JoAnne L. Flynn 1 , Mario Roederer 3 , Robert A. Seder 3 , Shelby O'Connor 2 , Charles A. Scanga 1 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 University of Wisconsin–Madison, Madison, WI, USA, 3 Vaccine Research Center, NIAID, Bethesda, MD, USA Background: The only licensed vaccine to prevent tuberculosis (TB) is BCG, a live attenuated M. bovis strain, given intradermally (ID) to infants at birth. While BCG ID confers protection against disseminated TB infection, it has more limited protection against pulmonary TB in adolescents and adults. Vaccination with BCG has been limited in HIV+ persons due to safety concerns related to BCG dissemination, even though TB is the major cause of morbidity and mortality in this population. BCG vaccine safety and efficacy can be assessed in macaques in the setting of SIV and M. tuberculosis (Mtb) infection. Recently, intravenous (IV) BCG was shown to prevent Mtb infection and disease in rhesus macaques and was associated with a sustained increase in lung T cells. Here, we used our established model of SIV/Mtb coinfection of Mauritian cynomolgus macaques (MCM) to determine whether IV BCG would be safe and effective at protecting chronic SIV+macaques from TB. Methods: We infected MCM intrarectally with SIVmac239. Five months later, they were vaccinated IV with 8x107 CFU BCG. Beginning 4 weeks later, vaccinated animals were treated with an 8-week regimen of isoniazid/rifampin/ ethambutol (HRE) to prevent potential disseminated BCG as well as to determine whether this BCG exposure period was sufficient to confer protection. Four weeks after stopping HRE treatment and 12 weeks after BCG IV, animals were challenged with low-dose (~10 CFU) Mtb Erdman via bronchoscope. Control animals consisted of SIV+ unvaccinated and SIV- vaccinated MCM that were all challenged with Mtb. Results: Administration of BCG IV in SIV+MCM resulted in a notable spike in plasma SIV followed by natural reestablishment of viral control. Even prior to HRE treatment, SIV+MCM exhibited no signs of disseminated BCG. Flow cytometry of BAL revealed a rapid and sustained increase in mycobacteria- specific, cytokine-producing T cells in airways following BCG vaccination in both SIV+ and SIV- animals. Following TB challenge, 18F-FDG PET/CT imaging showed rapid TB progression in unvaccinated, SIV+ animals but complete absence of inflammation in 6 of 7 BCG IV-vaccinated SIV+MCM. Remarkably, necropsy at 12 weeks after Mtb challenge showed the protected animals to be free of TB and without culturable bacilli in their tissues. Conclusion: These data show that IV BCG is safe, immunogenic, and extraordinarily protective in SIV+macaques. 732 EARLY BACTERICIDAL ACTIVITY OF MEROPENEM (+ AMOX/CLAV) WITH & WITHOUT RIFAMPIN FOR TB Veronique De Jager 1 , Ahmed A. Abufathi 2 , Hannelise Feyt 1 , Nikhil Gupte 3 , Naadira Vanker 1 , Grace Barnes 4 , Elana Van Brakel 1 , Eric Nuermberger 4 , Susan

Poster Abstracts

733 EFFECT OF RIFAMYCINS ON PRETOMANID EXPOSURE IN PATIENTS WITH PULMONARY TB Mahmoud T. Abdelwahab 1 , Elisa Ignatius 2 , Paolo Denti 1 , Kelly E. Dooley 3 , Nikhil Gupte 3 , Rodney Dawson 1 , Grace Barnes 3 , Kim Narunsky 1 , Bronwyn Hendricks 1 , for the APT Study Team 1 University of Cape Town, Cape Town, South Africa, 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: Pretomanid is a novel anti-TB nitroimidazole that was granted FDA approval for treatment of XDR TB this year. It may be a useful drug for treatment shortening for drug-sensitive TB, if delivered with other potent sterilizing drugs. Pretomanid is 20%metabolized by CYP3A4 isoenzyme. In healthy volunteers, rifampicin reduced pretomanid AUC by 66% (from 13.7 vs. 42.5 mg•h/L) but there are no data in patients to guide pretomanid and rifamycin co-administration. Methods: APT (Assessing Pretomanid for Tuberculosis) is a phase IIB RCT assessing the safety and efficacy of pretomanid added to first-line drugs over 12 weeks among patients with TB. Arm 1 received pretomanid 200 mg (Pa) plus isoniazid (H), rifampin (R), pyrazinamide (Z) for 8 weeks, followed by PaHR (weeks 9-12); Arm 2 received PaHRbZ for 8 weeks, followed by PaHRb (weeks 9-12); Arm 3 received standard therapy. This interim PK analysis includes 57

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