CROI 2019 Abstract eBook

Abstract eBook

Oral Abstracts

Oral Abstracts

84LB QT EFFECTS OF BEDAQUILINE, DELAMANID OR BOTH IN MDR-TB PATIENTS: THE DELIBERATE TRIAL

Kelly E. Dooley 1 , Susan L. Rosenkranz 2 , Francesca Conradie 3 , Laura E. Moran 4 , Richard Hafner 5 , Florian von Groote-Bidlingmaier 6 , Javier R. Lama 7 , Justin Shenje 8 , Kyla Comins 6 , Joel Morganroth 9 , Andreas H. Diacon 6 , Yoninah S. Cramer 2 , Kathleen M. Donahue 10 , Gary Maartens 8 , for the ACTG A5343 Study Team 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Harvard T.H. Chan School of Public Health, Boston, MA, USA, 3 University of the Witwatersrand, Johannesburg, South Africa, 4 Social & Scientific Systems, Silver Spring, MD, USA, 5 DAIDS, NIAID, Bethesda, MD, USA, 6 TASK Applied Science, Cape Town, South Africa, 7 Barranco Clinical Research Site, Lima, Peru, 8 University of Cape Town, Cape Town, South Africa, 9 ERT, Inc, Philadelphia, PA, USA, 10 Frontier Science & Technology Research Foundation, Inc, Amherst, NY, USA Background: Bedaquiline and delamanid are the first drugs of new classes approved for tuberculosis (TB) in 40 years. Both are oral, well-tolerated, and recommended for treatment of multidrug resistant (MDR) TB by WHO. However, these drugs and/or their metabolites have long half-lives, and each prolongs the QT interval with maximum effects weeks after drug initiation. The cardiac safety of these drugs given together as part of multidrug therapy has not been established. Methods: AIDS Clinical Trials Group (ACTG) A5343 is a phase 2, open-label trial randomizing adults with MDR-TB receiving multidrug background treatment (MBT) 1:1:1 to receive bedaquiline (BDQ arm), delamanid (DLM arm) or both (BDQ+DLM arm) for 24 weeks. Patients with QTcF >450ms or CD4 count < 100 cells/mm3 were excluded. HIV-infected participants received dolutegravir- based ART. Clofazimine was not allowed, and levofloxacin was given in place of moxifloxacin. Three electrocardiograms (ECG) were performed at baseline, every two weeks for 24 weeks, then week 28. QTcF (in ms) was calculated by a core laboratory blinded to treatment. The mean QTcF change from baseline (averaged over weeks 8-24) was defined in each arm, and the QTcF change in the BDQ+DLM armwas compared to QTcF changes in the BDQ and the DLM arms. Grade 3 QTcF prolongation was defined as >500ms or >480ms with increase from baseline >60ms. Grade 4 was life-threatening dysrhythmia. Results: Eighty-four participants were enrolled in South Africa and Peru. The majority (75%) were men; median age was 34 years; 37%were HIV-positive. Changes in QTcF from baseline, by week, including 4 weeks after stopping study drugs, are shown in the Figure. There were no Grade 3 or 4 QT interval prolongation events. Among 74 participants with QTc data (2062 unique ECGs, 688 visits, 69 participants with data through week 20, 64 with data through week 24), preliminary mean (95.1% CI) on-treatment QTcF value (in ms) was 410.3 (403.0, 417.7)(BDQ arm), 413.5 (406.1, 420.8)(DLM arm) and 412.5 (405.0, 420.0)(BDQ+DLM arm). Mean (95.1% CI) change (ms) in QTcF from baseline was 11.9 (7.4, 16.5) in the BDQ arm, 8.6 (4.0, 13.2) in the DLM arm, and 20.7 (16.1, 25.4) in the BDQ+DLM arm. Conclusion: The combined effect on the QTcF interval of co-administration of bedaquiline and delamanid is clinically modest and no more than additive. This study demonstrates the cardiac safety of the combined use of these drugs in patients with MDR-TB taking MBT with normal baseline QTcF values.

83 LONG-TERM MORTALITY AFTER TUBERCULOSIS CURE IN THE CIPRA HT-001 TRIAL Yvetot Joseph 1 , Marc Antoine Jean Juste 1 , Serena Koenig 2 , Sean Collins 1 , Zhiwen Yao 3 , Akanksha Dua 3 , Pierre Cremieux 3 , Patrice Severe 1 , Daniel Fitzgerald 4 , Jean William Pape 1 1 GHESKIO, Port-au-Prince, Haiti, 2 Brigham and Women’s Hospital, Boston, MA, USA, 3 Analysis Group, Inc, Boston, MA, USA, 4 Weill Cornell Medicine, New York, NY, USA Background: Although TB is a curable disease, studies from industrialized settings suggest an elevated risk of long-termmortality after TB recovery. Long-term outcomes data for individuals co-infected with TB and HIV from the developing world are limited. Methods: We conducted a retrospective analysis of 14-year follow-up data (2005-2018) for 703 adult HIV positive patients enrolled in the CIPRA HT-001 study at Les Centres GHESKIO, Haïti. Demographic and clinical data, including TB diagnosis, TB and HIV treatments were recorded in the study database and electronic medical records. The TB cohort was defined as patients with active TB at enrollment or incident TB during follow-up (cases). Time to death was estimated and cases and controls with no history of TB using Kaplan-Meier analysis and the log-rank test. We used univariate and multivariate Cox proportional hazards models to estimate hazard ratios for mortality. Time- varying ART status and CD4 count were included in the multivariate models. A period of 8-months post TB diagnosis was used to define the start of follow-up and exclude acute mortality from TB; additional sensitivity analyses using a longer period of 2-years were conducted. Results: 703 patients were included; 151 cases, and 573 controls. Baseline characteristics were similar in cases and controls. After exclusion of acute mortality on TB treatment, TB cases had lower survival rates, 5-year 82.3% vs 93.5%; 9-year 63.5% vs 83.9%, and lower median time to death (9.2 months vs median not reached, p<0.001) compared to controls (Figure 1). In univariate Cox models, the risk of death was higher for cases than controls (HR 2.9, 95% CI 1.8, 4.8, p<0.001). After adjusting for time-varying ART status and CD4 count, the risk of mortality remained significantly higher for cases (HR 3.6, 95% CI 2.1, 6.3, p<0.0001) however, time-varying ART and CD4 values were not independent predictors of mortality in that model. Mortality trends were similar in all sensitivity analyses. Conclusion: Patients with HIV who had TB coinfection had a higher risk for long-termmortality after TB-recovery compared to patients with no history of TB. CD4 count and time of ART initiation were not independently associated with risk of mortality in this model. Long-termmortality risk after TB treatment among HIV positive patients should be thoroughly documented to elucidate the mechanisms and assess its impact on mortality.

32

CROI 2019