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Response Rate, Resistance, and Side Effects After 96 Weeks of TMC278
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
TMC278, an investigational nonnucleoside, kept pace with efavirenz in virologic response through 96 weeks of a phase 2 trial [1]. The new nonnuke had a somewhat better safety profile than efavirenz and a more diverse array of resistance-related mutations upon failure, which was rare with either drug. The choice between these two stalwart antiretrovirals may come down to a balance between the moderately lower side effect risk with TMC278 and the convenience of giving efavirenz as part of a one-pill, once-a-day, three-drug regimen.
Researchers in Europe, South Africa, and Thailand randomized 367 previously untreated people to efavirenz or one of three TMC278 doses--25, 75, or 150 mg once daily. Everyone also began one of two fixed-dose nucleoside duos, zidovudine/lamivudine or tenofovir/emtricitabine. Because 25 mg of TMC278 controlled HIV as well as higher doses, phase 3 trials are evaluating 25 mg.
At week 96 sub-50-copy response rates were similar with 25 mg of TMC278 (76%) and efavirenz (71%) in a time-to-loss-of-virologic-response analysis. Viral control by this measure hardly waned with either drug from week 48 through week 96. CD4 counts continued to climb from pretreatment values over that interim, from +122 to +146 with 25 mg of TMC278 and from +127 to +160 with efavirenz.
Treatment failed virologically in only 17 of 279 people (6%) taking TMC278 and 6 of 89 (7%) taking efavirenz. Among people with genotyping results after failure, 9 of 16 (56%) in whom TMC278 failed and 3 of 5 (60%) in whom efavirenz failed had treatment-induced nonnucleoside resistance mutations. Because of these low failure and resistance rates, the investigators said "no definitive TMC278 resistance profile could be determined." It is perhaps interesting, though, that only two mutations emerged in 3 efavirenz failures (103N and 106M), while 8 mutations emerged in 9 TMC278 failures (100I, 101E, 103N, 108I, 138K, 138R, 181C, and 230L). Given the small number of people with treatment-induced mutations in either group, however, it is probably not prudent to make too much of that difference now.
Any grade 2 to 4 side effect arose in 33 of 89 people (37%) taking efavirenz and 56 of 279 people (20%) taking TMC278 (P = 0.003). But rates of side effects leading to treatment discontinuation were similar in the two groups (9% with efavirenz and 12% with TMC278).
Neurologic and psychiatric problems affected a bigger proportion of people taking efavirenz than TMC278 (60% versus 33% for neurologic problems, P < 0.01; 21% versus 16% for psychiatric problems). The great bulk of these conditions in either group were rated grade 1 or grade 2.
Any grade of rash possibly related to treatment affected 11 of 89 people (12%) taking efavirenz and 3 of 279 (1%) taking TMC278, a significant difference (P < 0.0001). Half of the rashes possibly induced by efavirenz were grade 1 and half were grade 2. Grade 3 or 4 lab abnormalities were rare in any treatment arm and comparable among arms. Total-to-high-density lipoprotein cholesterol ratio improved in both TMC278 takers and efavirenz takers throughout the study. Triglycerides fell by an average 10 mg/dL in the TMC278 groups while rising 29 mg/dL in the efavirenz groups. Although this difference is statistically significant (P < 0.01), it may be clinically irrelevant. The investigators did not report pretreatment triglycerides in their poster.
Reference
1. Molina JM, Cordes C, Ive P, et al. Efficacy and safety of TMC278 in treatment-naive, HIV-infected patients: week 96 data from TMC278-C204. International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P002.
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