CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

29LB SYSTEMATIC VS TEST-GUIDED TUBERCULOSIS TREATMENT: DATA OF THE STATIS RANDOMIZED TRIAL François-Xavier Blanc 1 , Anani D. Badje 2 , Maryline Bonnet 3 , Delphine Gabillard 2 , Eugène Messou 4 , Conrad Muzoora 5 , Sovannarith Samreth 6 , Duc Bang Nguyen 7 , Laurence Borand 8 , Anaïs Domergue 7 , Naome Natukunda 9 , Serge Eholie 10 , Serge Domoua 10 , Xavier Anglaret 2 , Didier Laureillard 11 1 CHU de Nantes, Nantes, France, 2 INSERM, Bordeaux, France, 3 IRD, Montpellier, France, 4 INSERM, Abidjan, Côte d’Ivoire, 5 Mbarara University of Science and Technology, Mbarara, Uganda, 6 National Centre for HIV/AIDS Dermatology and STDs, Phnom Penh, Cambodia, 7 Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam, 8 Pasteur Institute in Cambodia, Phnom Penh, Cambodia, 9 Epicentre, Mbarara, Uganda, 10 Université Félix Houphouët-Boigny, Abidjan, Côte d’Ivoire, 11 CHU de Nimes, Nimes, France Background: Despite increasing access to antiretroviral therapy (ART), many HIV+ adults still present for care with severe immunosuppression. In such late presenters, mortality following ART initiation is high, curable diseases like tuberculosis (TB) or invasive bacterial diseases (IBD) being major causes of mortality. Here, we report the results of the STATIS open-label randomized controlled trial (ANRS 12290, NCT02057796) that compared the efficacy and safety of 2 strategies aiming at decreasing mortality and IBD in late presenters. Methods: The trial was conducted in Côte d’Ivoire, Uganda, Cambodia and Vietnam. ART-naïve HIV-1 infected adults with CD4<100 cells/µl ready to start ART were randomly assigned to either ART + extensive TB screening (arm 1) or ART + systematic empirical TB treatment (4HRZE/2HR) (arm 2). In arm 1, extensive TB screening included Xpert MTB/RIF on sputum, urine lipoarabinomannan (LAM) and chest X-ray at baseline and at any time during follow-up in case of TB symptoms. ART was initiated immediately in patients who did not start TB treatment at baseline (arm 1 patients with negative TB screening) and 2 weeks after starting TB treatment in others (arm 1 patients with positive TB screening and arm 2 patients). The primary outcome was the occurrence of death or IBD at week 24 (W24). Total follow-up lasted 48 weeks. We used Cox models to compare the probability of outcomes between arms, adjusting for randomization stratification variables (country and CD4 level). Results: Between Sep. 2014 and May 2017, 1047 participants were included (arm 1: 525; arm 2: 522; 56% from Africa; 44% from South-East Asia). The last one reached W24 in Nov. 2017. Baseline characteristics were: 58%male, mean (SD) age 36 (9) years, body mass index 20.1 (3.5) kg/m2, hemoglobin 11.6 (2.3) g/dl, CD4 36 (27) cells/µl, plasma HIV RNA 5.4 (0.6) log 10 copies/ml, with no difference between arms. At W24, 39 patients (3.8%) were lost to follow-up (arm 1: 21; arm 2: 18), while there were 69 deaths (arm 1: 36; arm 2: 33) and 29 IBD (arm 1: 14; arm 2: 15) (Figure). The W24 hazard ratio of events between arm 2 vs. arm 1 was 0.93 (95%CI 0.61-1.42) for death or IBD, 0.92 (0.57-1.48) for death alone, 1.14 (0.54-2.40) for IBD alone and 2.70 (1.80-4.04) for grade 3-4 drug-related toxicity. Conclusion: Systematic TB treatment is not superior to extensive TB screening using Xpert MTB/RIF and urine LAM and targeted TB treatment to decrease the risk of mortality or IBD in ART-naïve adults ready to start ART with CD4<100/µl.

28LB RIFAMPIN EFFECT ON TENOFOVIR ALAFENAMIDE (TAF) PLASMA/ INTRACELLULAR PHARMACOKINETICS Maddalena Cerrone 1 , Omamah Alfarisi 2 , Megan Neary 3 , Mark A. Marzinke 2 , Teresa Parsons 2 , Andrew Owen 3 , Gary Maartens 4 , Anton Pozniak 1 , Charles W. Flexner 2 , Marta Boffito 1 1 Chelsea and Westminster Hospital, London, UK, 2 The Johns Hopkins University, Baltimore, MD, USA, 3 University of Liverpool, Liverpool, UK, 4 University of Cape Town, Cape Town, South Africa Background: TAF produces lower plasma and higher intracellular (IC) tenofovir (TFV) concentrations than tenofovir disoproxil fumarate (TDF), but is a substrate of drug transporters (e.g. BCRP; ABCG2; ABCB1) and therefore a potential victim of drug interactions, especially with inducers like rifampin (RIF) that act via nuclear receptors such as PXR (NR1I2) and CAR (NR1I3). Methods: This study is the first to measure the pharmacokinetics (PK) of TAF once-daily (OD) with RIF and compare it directly to TDF. Healthy volunteers aged 18-65 years received TAF/ FTC 25/200mg OD (28 days) with food, followed by TAF/FTC+RIF 600mg OD (28 days, RIF on empty stomach followed by TAF/ FTC with meal after 30 mins), followed by TDF 300mg OD (28 days) with food. Intensive PK sampling occurred on days 28 (TAF/FTC), 56 (TAF/FTC+RIF) and 84 (TDF), and plasma TAF, TFV, FTC and IC TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were measured by validated LC-MS methods. Subjects were genotyped for polymorphisms in NR1I2 (rs2472677), NR1I3 (rs2307424), CYP3A4 (rs35599367), and ABCG2 (rs2231142). Results: 17 subjects completed all PK phases (14 females). Plasma TAF and TFV geometric mean ratios (GMR, TAF+RIF vs TAF) and 90% confidence intervals (CI) for the main PK parameters calculated are illustrated in the Table, as well as IC TFV-DP GMR (90%CI). Mean TFV-DP AUC was 122,920 on PK2 versus 24,247 h*fmol/million-cells on PK3. Plasma TFV/IC TFV-DP AUC ratio was unchanged by RIF co-administration (0.001), suggesting that RIF mainly affects TAF absorption and not clearance. FTC-TP PK parameters were not affected by RIF. All polymorphisms were in Hardy-Weinberg equilibrium, and no consistent associations were observed after correction for multiple comparisons. Conclusion: Relative to TAF 25mg OD, following administration of TAF OD with RIF, plasma TAF Cmax and AUC were decreased by 45% and 47%, respectively, while IC TFV-DP concentrations were decreased by 40%. However, IC TFV-DP

Oral Abstracts

concentrations were still 82% higher on average than those achieved by standard dose TDF. These data support further study of TAF when co- administered with RIF in patients with HIV and tuberculosis.

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CROI 2018