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Title
Virologic efficacy of raltegravir vs. efavirenz-based antiretroviral treatment in HIV1-infected adults with tuberculosis: W48 results of the ANRS 12300 Reflate TB2 trial
Presenter
Nathalie De Castro
Authors
N. De Castro1, O. Marcy2, C. Chazallon2, E. Messou3, S. Eholié4, N. Bhatt5, C. Khosa5, D. Laureillard6, G. Do Chau7, V. Veloso8, C. Delaugerre1, X. Anglaret2, J.-M. Molina1, B. Grinsztejn8, for the ANRS 12300 Reflate TB2 study group
Institutions
1APHP- Hopital Saint Louis, Paris, France, 2University of Bordeaux, Bordeaux Population Health Centre Inserm U1219, Bordeaux, France, 3CEPREF, Abidjan, Cote D'Ivoire, 4SMIT, Abidjan, Cote D'Ivoire, 5Instituto Nacional de Saúde, Maracuene, Mozambique, 6CHU de Nîmes, Nîmes, France, 7Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam, 8Oswaldo Cruz Foundation - FIOCRUZ, Rio de Janeiro, Brazil

Background: Double-dose raltegravir is recommended in HIV1-infected patients with tuberculosis. A previous phase 2 study showed similar efficacy of standard raltegravir 400mg BID, raltegravir 800mg BID, or efavirenz-based regimens. We aimed to assess non-inferiority of raltegravir 400mg BID to efavirenz in HIV1-infected patients with tuberculosis.
Methods: ANRS 12300 Reflate TB2 is an open-label, phase 3, randomized trial conducted in Brazil, Côte d''Ivoire, France, Mozambique, and Vietnam. ART-naïve HIV1-infected patients aged ≥18 years on standard tuberculosis treatment for 2-8 weeks were randomized (1:1) to receive raltegravir 400mg BID or efavirenz 600mg QD both with TDF/3TC 300mg/300mg QD. The primary endpoint was the proportion of patients with virologic success at week 48 defined as HIV-RNA ≤50 cp/ml on allocated therapy using the FDA snapshot algorithm. The pre-specified non-inferiority margin was 12%.
Results: From September 2015 to January 2018, 230 patients were randomized in each trial arm: 201 (87%) and 203 (88%) completed follow-up in the EFV and RAL arms, respectively. Median age was 35 (IQR: 29-43) years, 40% were female, median BMI 19.1 (IQR: 17.5-21.0) kg/m2, median CD4 102 (IQR: 38-239) cells/µL, median HIV-RNA was 5.5 log (IQR: 5.0-5.8), 311 (68%) patients had pulmonary tuberculosis only, and 308 (68%) had bacteriologically-confirmed tuberculosis. In the mITT population, virologic success was achieved: in 134/228 (59%) pts in the raltegravir arm and 135/227 (59%) pts in the efavirenz arm at W24 (end of TB treatment); in 139/228 (61%) patients in the raltegravir arm and 150/227 (66%) patients in the efavirenz arm at W48. At W48, the difference between the raltegravir and efavirenz arm was -5.1% (95% CI: -13.9- +3.7), thus not meeting criteria for non-inferiority. Sixty-two (27%) and 77 (33%) patients experienced grade 3-4 adverse events in the raltegravir and efavirenz arms, respectively (p-value=0.1), including 11 (5%) and 13 (6%) IRIS (p-value=0.7). Twelve (5%) patients in the raltegravir arm and 14 (6%) in the efavirenz arm died (Logrank p-value=0.7).
Conclusions: The non-inferiority of raltegravir 400mg compared to efavirenz at week 48 was not demonstrated. Raltegravir remains a safe option in combination with tuberculosis treatment. Complementary analyses are necessary to identify determinants of virologic failures in both arms.