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.