Etravirine (TMC-125) associated with -1 log viral load reduction at 48-weeks results in treatment experienced patients
Simon Collins, HIV i-Base
Cal Cohen from Community Research Initiative of New England, Boston reported 48-week results from the Tibotec randomised, controlled, Phase II study of etravirine (TMC-125) in 199 treatment experienced patients with documented NNRTI resistance and 3 or more primary PI mutations.
Patients were randomised to TMC125 (400 mg or 800 mg bid) with an investigator selected background, or standard-of-care control regimen. Median baseline CD4 and viral load were 100 cells/mm3 and 4.7 log copies/mL respectively.
Mean reductions viral load (ITT, NC=F) were -0.88, -1.01 and -0.14 logs for the 400mg, 800mg and control arms respectively (p<0.05 for both TMC doses compared to control). CD4 cell counts increased by +58, +61 and +13 cells/mm3, for the 400mg, 800mg and control arms respectively.
The study design allowed patients with virological failure in the control group to leave the study after 16 weeks and access etravirine on an open-label basis. This confounded the comparison of safety by the lower median duration of treatment in the control arm of 17.9 weeks, versus 47.7 weeks in both TMC125 groups. Grade 3/4 side effects (all causes) were reported in 43% of patients on TMC125 and 17% patients discontinued etravirine due to side effects.
The principle importance of etravirine is the response to NNRTI-experienced patients. At baseline, patients had a median of 2 NNRTI mutations and the phenotypic median fold-change to efavirenz, nevirapine and etravirine was 41, 61, and 1.7-fold, respectively. The virologic response by number of NNRTI mutations at baseline is shown for the 800mg group is shown in Table 2.
Table 1: Results of etravirine (TMC-125) at 48-weeks
|Mean VL change (log)||-0.88*||-1.01||-0.14|
|Mean CD4 change (log)||+58||+66||+13|
|Median duration of Rx (wks)||48||48||18|
* p <0.05 compared to control
Table 2: Response to 800mg BID etravirine by baseline NNRTI resistance
|# mutations||0||1||2||3 or more|
|N (%)||14 (18%)||19 (24%)||16 (20%)||30 (38%)|
|Mean decrease VL||-1.67||-1.38||-0.90||-0.54|
No single NNRTI mutation was associated with an arbitrary >10-fold mean change, although clinical cut-offs for etravirine still have to be established from larger trials. 12% patients had a combination of mutations that generated >10-fold reduced susceptibility to etravirine, always including one or more from K101P, V179E/F, Y181I/V G190S and M230L, and always with at least 4 other mutations.
The dose selected for Phase III studies is 800mg BID, which requires 2 x200mg pills, twice-daily.
- Cohen C, Steinhart C, Ward D et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. Abstract TUPE0061.