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No Dose Adjustment With Etravirine Plus ATV/r in Treatment Experienced: Randomized Trial
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
After 48 weeks of the randomized TEACH trial, virologic responses were equivalent when antiretroviral-experienced people took standard-dose etravirine with 300/100 or 400/100 mg of atazanavir/ritonavir daily [1]. Atazanavir concentrations were only slightly lower with the 300/100-mg dose than with 400/100 mg, and the researchers concluded no dose adjustment is necessary in treatment-experienced people.
A study in healthy volunteers using the phase 2 etravirine formulation found that atazanavir/ritonavir increased etravirine minimum concentration (Cmin), maximum concentration (Cmax), and area under the concentration-time curve (AUC), while etravirine lowered atazanavir Cmin and AUC [2]. To assess interactions between etravirine and two doses of atazanavir/ritonavir in antiretroviral-experienced people taking the current etravirine formulation, researchers in South Africa and the United States conducted the randomized, open-label TEACH trial.
During a 2-week lead-in phase, study participants took 300/100 mg of atazanavir/ritonavir once daily plus two investigator-selected nucleosides. Tenofovir was not allowed. Then the investigators randomized people to (1) continue 300/100 mg of atazanavir/ritonavir and replace one nucleoside with 200 mg of etravirine twice daily or (2) switch to 400/100 mg of atazanavir/ritonavir once daily and replace one nucleoside with 200 mg of etravirine twice daily. The investigators measured atazanavir concentrations at the end of the 2-week lead-in and measured atazanavir and etravirine levels 2 weeks after randomization. They used a noncompletion-equals-failure analysis to determine the proportion of participants with a viral load below 50 copies at 48 weeks.
The TEACH team randomized 25 people to each study arm after the 2-week lead-in. About half in both groups were women. Median age stood at 39 in the 300/100 group and 40 in the 400/100 group, median pretreatment CD4 count at 186 and 238, and median pretreatment viral load at 4.1 log10 copies in both groups. The 300/100 group had a lower proportion of blacks or African Americans than the 400/100 group (48% versus 72%). Most study participants (91%) had taken at least one nonnucleoside; 41% in the 300/100 group and 27% in the 400/100 group had taken a protease inhibitor (PI). Respective rates of baseline etravirine mutations were 53% and 33%, any nonnucleoside mutation 100% and 100%, and any primary PI mutation 19% and 5%.
With 300/100 mg of atazanavir/ritonavir plus etravirine, atazanavir Cmin, Cmax, and AUC were 18%, 4%, and 4% lower than without etravirine. With 400/100 mg of atazanavir/ritonavir plus etravirine, atazanavir Cmin decreased 9% and Cmax increased 5% more than without etravirine, and coadministration had no impact on atazanavir AUC. Compared with historical controls, etravirine Cmin, Cmax, and AUC were 7%, 6%, and 24% higher with 300/100 mg of atazanavir/ritonavir. With 400/100 mg of atazanavir/ritonavir, etravirine Cmin, Cmax, and AUC were 17%, 13%, and 16% lower than in historical controls.
Adverse event rates were similar in the two treatment arms, with 5 in each arm (23%) having any treatment-related event, 4 in each arm (18%) have a grade 3 or 4 event, and 2 in each arm (9%) stopping treatment because of an adverse event. Four people in the 300/100 group and 2 in the 400/100 group had a serious adverse event (18% versus 9%). Rates of hepatotoxicity in the 300/100 and 400/100 groups were 23% and 23%, hyperbilirubinemia 38% and 29%, rash 14% and 9%, and neuropsychiatric problems 14% and 0%.
At 48 weeks 50% in the 300/100 arm and 45% in the 400/100 arm had a viral load below 50 copies by the noncompletion-equals-failure analysis, a nonsignificant difference (P = 0.692). Viral load fell by an average 1.4 log in both treatment arms. There were 7 virologic failures in the 300/100 group (3 nonresponders and 4 rebounders) and 6 in the 400/100 arm (1 nonresponder and 5 rebounders). Nine nonnucleoside mutations emerged in the 13 people with virologic failure, with seven of the mutations in one person each. Atazanavir-associated mutations arose only in the 300/100 group: L10F in 1, V32I in 1, M46I in 2, and V82A in 1. CD4 counts rose by an average 105 cells in the 300/100 group and 132 cells in the 400/100 group. The researchers did not report adherence findings.
The TEACH investigators concluded that the interaction between etravirine and atazanavir was less in these antiretroviral-experienced people than in healthy volunteers [2]. Safety, virologic response, and CD4 response were similar in both treatment arms, and virologic response rates were similar to those seen in previous studies of people with comparable antiretroviral experience. The researchers proposed that standard-dose etravirine can be administered with 300/100 mg of atazanavir/ritonavir without dose adjustment in antiretroviral-experienced people.
References
1. Orrell C, Felizarta F, Nell A, et al. Etravirine 200 mg twice-daily combined with atazanavir/ritonavir 300/100 mg or 400/100 mg once-daily in treatment-experienced patients: primary 48-week efficacy and safety analysis of the TEACH trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WEPE519.
2. Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 2010;15:817-829.
IAS: Etravirine 200mg twice daily combined with atazanavir/ritonavir 300/100mg or 400/100mg once daily in treatment-experienced patients: primary 48-week efficacy and safety analysis of the TEACH trial - (07/13/13)
IAS: Intelence and prezista Once A Day Study (INROADS): A Multicenter, Single-Arm, Open-Label Study of Once Daily Combination of Etravirine (ETR) and Darunavir/Ritonavir (DRV/r) as Dual Therapy in Early Treatment-Experienced Subjects - (07/13/13)
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