CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

78 SIX-MONTH IPT REDUCES MORTALITY INDEPENDENTLY OF ART IN AFRICAN ADULTS WITH HIGH CD4 Anani D. Badje 1 , Raoul Moh 2 , Delphine Gabillard 1 , Calixte Guehi 3 , Mathieu Kabran 2 , Hervé Menan 2 , André Inwoley 2 , Christine Danel 1 , Serge Eholie 4 , Xavier Anglaret 1 1 INSERM, Bordeaux, France, 2 Prog PAC-CI, ANRS Rsr site, Abidjan, Cote d’Ivoire, 3 INSERM, Abidjan, Cote d’Ivoire, 4 Service des Maladies Infectieuses et Tropes, Abidjan, Cote d’Ivoire Background: Temprano was a factorial 2x2 trial that assessed the benefits of early antiretroviral therapy (ART) and 6-month isoniazid prophylaxis (IPT) among HIV-infected adults in Côte d’Ivoire. Participants were randomly assigned to four groups (deferred-ART- No-IPT, deferred-ART-plus-IPT, early-ART-No-IPT, early ART-IPT). Early ART and IPT were shown to independently reduce the risk of severe morbidity at 30 months. Here we present the efficacy of IPT in reducing mortality in the long term. Methods: Participants who completed the trial follow up were invited to participate in a post trial phase (PTP). The PTP endpoint was death in an intention-to-treat analysis. We used Cox proportional models to compare mortality between the IPT and No-IPT strategies from inclusion in Temprano to January 2015. Results: 2,056 patients (mean baseline CD4 count 477/mm3) were followed for 9,404 patient-years (Temprano 4,757; PTP 4,647). A total of 86 deaths were observed (Temprano 47; PTP 39), 34 in patients randomized to IPT (six-year probability 4.1%, 95% CI 2.9 to 5.7) and 52 in those randomized to No-IPT (six-year probability 6.9%, 95% CI 5.1 to 9.2). The hazard ratio of death for IPT compared to No-IPT was 0.63 (95% CI, 0.41 to 0.97) after adjusting for the ART strategy (Early vs. Deferred), and 0.61 (95% CI, 0.39 to 0.94) after adjusting for the ART strategy, baseline CD4 count and other key factors. Conclusion: In these African HIV-infected adults with high CD4 counts, 6-month IPT led to a 39% decrease in mortality, independently of ART initiation and baseline CD4 count. 79 THE ESSENTIALITY OF INH DURING THE FIRST 14 DAYS OF TB THERAPY: THE A5307 EBA TRIAL Andreas H. Diacon 1 , Sachiko Miyahara 2 , Xin Sun 2 , Richard Hafner 3 , Florian von Groote-Bidlingmaier 4 , Courtney Fletcher 5 , Evelyn Hogg 6 , Rodney Dawson 7 , Susan Swindells 5 , William Bishai 8 1 Stellenbosch Univ, Cape Town, South Africa, 2 Harvard Univ, Boston, MA, USA, 3 NIH, Bethesda, MD, USA, 4 TASK Applied Sci, Cape Town, South Africa, 5 Univ of Nebraska Med Cntr, Omaha, NE, USA, 6 Social &Scientific Systems, Silver Spring, MD, USA, 7 Univ of Cape Town, Mowbray, South Africa, 8 The Johns Hopkins Univ, Baltimore, MD, USA Background: Clinical and animal model studies suggest that isoniazid contributes a significant level of early bactericidal activity (EBA) during the initial 2 days of treatment, but the bactericidal rates decline significantly beginning at day 3 in patients with uncomplicated, smear-positive pulmonary tuberculosis. Methods: We conducted a 14-day randomized phase II early bactericidal activity (EBA0-14) trial to determine how isoniazid (INH) affects EBA in combination with rifampicin, pyrazinamide, and ethambutol (RZE). Four study arms included (1) isoniazid, rifampicin, pyrazinamide, and ethambutol (RHZE) for 14 days, (2) RHZE for 2 days and omitting INH for days 3-14, (3) RHZE for 2 days and replacing INH with moxifloxacin for days 3-14, and (4) RZE for 14 days. EBA0-14 was measured by: (1) rate of M. tuberculosis decline per day in sputum by colony forming unit (CFU) count [primary endpoint], and (2) increase in time to positivity in liquid culture [secondary endpoint]. Results: Of the 69 randomized participants, 63 completed the study with 15-17 participants in each study arm. Most participants (83%) were male and HIV-negative (94%); median age was 31 and median BMI was 18.9. EBA0-14 was not different across all arms (figure 1). The mean baseline bacterial sputum load for all participants was 5.80 log10CFU (Standard Deviation [SD] 0.98) and the median daily decline in CFU count over 14 days was 0.12 log10CFU (Inter Quartile Range [IQR] 0.06 to 0.17). The mean baseline time to culture positivity in liquid mediumwas 109 hours (SD 29) and the median daily increase in time to positivity was 12 hours (IQR 9 to 16). EBA0-2 in the arms containing INH was not different compared to the armwithout INH, and the median daily decline in CFU count over 2 days for all participants was 0.16 log10CFU (IQR -0.09 to 0.47). Exploratory sub-analysis revealed that participants with higher sputum baseline loads had higher initial EBA irrespective of treatment. Grade 3 or 4 adverse events were rare and not significantly different across arms. Conclusion: The EBA over 14 days for all study arms was not different from each other. INH did not appear to significantly add to the 14-day EBA observed with RZE. Unlike earlier studies, significant EBA over 2 days due to INH was not observed. The absence of the expected bi-phasic INH response might be due to the relatively low baseline bacterial load in this study. Lower bacterial loads have been reported in recent EBA studies and it is likely due to early detection of TB.

Oral Abstracts

80LB THE NIX-TB TRIAL OF PRETOMANID, BEDAQUILINE AND LINEZOLID TO TREAT XDR-TB Francesca Conradie 1 , Andreas H. Diacon 2 , Daniel Everitt 3 , Carl Mendel 3 , Christo van Niekerk 4 , Pauline Howell 5 , Kyla Comins 6 , Mel Spigelman 3 1 Univ of the WItswatersrand, Johannesburg, South Africa, 2 Stellenbosch Univ, Cape Town, South Africa, 3 Global Alliance for TB Drug Development, New York, NY, USA, 4 Global Alliance for TB Drug Development, Pretoria, South Africa, 5 Clinical HIV Rsr Unit, Johannesburg, South Africa, 6 TASK Applied Science, Belville, South Africa Background: Patients with Extensively Drug Resistant (XDR) tuberculosis (TB) have had limited options for treatment and high mortality. Nix-TB is an ongoing open label study in South Africa of bedaquiline (400 mg qd for 2 weeks followed by 200 mg tiw), pretomanid (200 mg qd) and linezolid (1200 mg qd) given orally for 6 months. Methods: Participants are required to have documented XDR-TB, or MDR TB treatment intolerance or failure (TI or Fr). The primary endpoint is bacteriologic failure, relapse or clinical failure at 6 months after treatment. Participants who are culture positive at 4 mos treatment may extend treatment for 3 mos. Clinical, laboratory and sputum liquid culture evaluations are performed at baseline and wks 1, 2, 4, 6, 8 and then every 4-6 wks through treatment. Eye examinations with slit lamp are made 3 times. Participants who complete treatment are followed for 24 mos after treatment end with repeat clinical assessments and sputum cultures. Results: Since April 2015, 61 participants have been enrolled as of 15 December 2016 at 2 sites. 49% of the participants are HIV positive, 79% have XDR-TB and 21% have MDR TI or Fr to prior therapy. 34 have completed the 6 months of therapy with the drug regimen and 20 have been followed to the primary endpoint at 6 months after treatment. All surviving patients were culture negative by 4 mos, with 74% negative at 8 wks. 4 participants died within the first 8 wks of therapy; 3 had multi-organ TB on autopsy and 1 had a GI bleed due to erosive esophagitis. 27% had serious adverse events (AE). No surviving participants have withdrawn from the study due to any clinical AE or lab abnormalities. The expected linezolid toxicities of peripheral neuropathy (PN) and myelosuppression (MSPN) were common but manageable. 71%, of participants had at least one linezolid dose

31

CROI 2017