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Twice-Daily 400-mg Raltegravir Not Noninferior to Efavirenz for HIV With TB – “Virologic efficacy of raltegravir vs. efavirenz-based antiretroviral treatment in HIV1-infected adults with tuberculosis: W48 results of the ANRS 12300 REFLATE TB2 trial”
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10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City
Mark Mascolini
A regimen including 400 mg of raltegravir twice daily did not meet noninferiority criteria compared with 600 mg of efavirenz once daily for HIV with TB coinfection in a randomized 5-country trial [1]. REFLATE TB2 investigators concluded that efavirenz remains the preferred first-line therapy for HIV in people with TB.
Because of toxicity and HIV resistance issues with efavirenz, researchers are evaluating integrase inhibitors for treatment of HIV infection in people with tuberculosis. Both raltegravir and dolutegravir interact with rifampin, but doubling the integrase inhibitor dose may overcome that interaction. INSPIRING, a 113-person noncomparative, active-control, randomized, open-label study found 50 mg of dolutegravir twice daily generally effective and well tolerated in people taking rifampin for TB [2].
The phase 2 REFLATE TB trial found similar anti-HIV efficacy with 400 mg of raltegravir twice daily, 800 mg of raltegravir twice daily, and efavirenz [3]. The phase 3 open-label REFLATE TB2 randomized 460 rifampin-treated people to 400 mg of raltegravir twice daily or 600 mg of efavirenz once daily (both with once-daily TDF/3TC). Participants in Brazil, Cote d'Ivoire, France, Mozambique, and Vietnam had to be adults naive to antiretrovirals and have confirmed or probable TB.
The primary endpoint was the proportion of participants in each arm with a viral load below 50 copies by the FDA snapshot algorithm at 48 weeks. Researchers set the noninferiority margin at 12%.
Among 228 people randomized to raltegravir and 227 randomized to efavirenz, median age stood at 34 and 37 years, pretreatment CD4 count at 98 and 108, and pretreatment viral load at 5.5 log (about 316,000 copies). About 40% in each treatment arm were women, and one third in each arm had extrapulmonary TB. Similar proportions completed the study in the raltegravir group (87%) and the efavirenz group (88%).
Snapshot analysis at week 48 determined that 61% randomized to raltegravir and 66% randomized to efavirenz had a viral load below 50 copies. This difference did not meet noninferiority criteria (difference -5.1, confidence interval -13.9 to 3.7). Proportions meeting criteria for virologic failure were 29% with raltegravir an 22% with efavirenz. Proportions with a 48-week viral load below 50 copies were similar with raltegravir and efavirenz when the pretreatment load lay below 100,000 copies (75% and 73%) but lower with raltegravir than efavirenz in people who started therapy with more than 100,000 copies (58% versus 64%). Median CD4 gains through 48 weeks did not differ substantially between raltegravir and efavirenz (183 and 172).
Adverse event rates were similar with raltegravir and efavirenz, including grade 3 or 4 events (27% and 30%), drug-related events (11% and 10%), drug-related events leading to discontinuation (under 1% in both groups), and immune reconstitution inflammatory syndrome (IRIS) (4% and 6%).
REFLATE TB2 investigators suggested that 400 mg of raltegravir twice daily may be "an alternative" for some people with HIV/TB coinfection. But efavirenz remains the preferred first-line regimen.
References
1. De Castro N, Marcy O, Chazallon C, et al. Virologic efficacy of raltegravir vs. efavirenz-based antiretroviral treatment in HIV1-infected adults with tuberculosis: W48 results of the ANRS 12300 REFLATE TB2 trial. 10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City. Abstract MOAB0101.
2. Dooley KE, Kaplan R, Mwelase N, et al. Dolutegravir-based antiretroviral therapy for patients co-infected with tuberculosis and HIV: a multicenter, noncomparative, open-label, randomized trial. Clin Infect Dis. 2019. pii: ciz256. doi: 10.1093/cid/ciz256.
3. Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 REFLATE TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014;14:459-467.
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