DUET studies clarify antiviral efficacy of etravirine and cross-resistance profile to other NNRTIs
3 September 2007. Related: Conference reports, Antiretrovirals, IAS 4th Sydney 2007.
Simon Collins, HIV i-Base
Results from the DUET study were presented as two late-breaker presentations. [1, 2] Both studies have identical design and similar results. They were also both published in full in the 7 July 2007 issue of the Lancet.
DUET 1 was run in USA, Mexico, South Africa, Thailand and South America and DUET 2 was run in Australia, Europe and the USA.
Each study included approximately 600 triple-class experienced patients on stable (failing) therapy with viral load >5000 copies/mL using darunavir plus optimised background therapy who were randomised to either etravirine (200mg twice daily) or placebo. Randomisation was stratified by history of T-20 use, darunavir use, and baseline viral load + 30,000 copies/mL. Primary endpoint was suppression to <50 copies/mL at 24 weeks.
Median (range) baseline viral load and CD4 count were comparable between arms: 4.8-4.9 log, (2.2-6.8 log) and 105 cells/mm3 (1-900 cells/mm3) respectively, with 55-62% patients CDC category C and 25% using T-20 for the first time. Around 12% patients were coinfected with HBV or HCV.
Approximately 95% patients had > 3 primary PI mutations including 40% with > 3 darunavir-associated mutations. 90% > 1 NNRTI associated mutations including 20% with > 4 NNRTI-associated mutations. Over 90% patients had > 4 NRTI-associated mutations.
Patients receiving etravirine had an additional -0.5 log drop in viral load and were approximately 30% more likely to reach <400 and <50 copies/mL, and are detailed in Tables 1 and 2.
Table 1: Week 24 efficacy in DUET 1
| TMC125 | Placebo | Diff (95% CI) | |
|---|---|---|---|
| <50 copies/mL | 56% | 39% | 17% (9%; 25%)* |
| <50 (BL < 100,000) | 68% | 47% | 21% (not given) |
| <50 (BL < 100,000) | 38% | 27% | 11% (not given) |
| <400 copies/mL | 74% | 51% | 22% (15%; 30%)* |
| Mean (SE) change in viral load (log10) | -2.41 (0.074) | -1.70 (0.085) | 0.57 (0.33; 0.82)** |
| Mean (SE) change in CD4 cell count | 89.0 (5.83) | 64.4 (5.22) | 31.7 (15.2; 48.2) |
* p<0.001 logical regression model; ** p<0.0001
Table 2: Week 24 efficacy in DUET 2
| TMC125 | Placebo | Diff (95% CI) | |
|---|---|---|---|
| <50 copies/mL | 62% | 44% | 18% (11%; 26%)* |
| <400 copies/mL | 75% | 54% | 21% (14%; 29%)* |
| Mean (SE) change in viral load (log10) | -2.34 (0.076) | -1.68 (0.081) | 0.51 (0.28; 0.74)** |
| Mean (SE) change in CD4 cell count | 78.1 (4.87) | 65.5 (4.72) | 6.59 (-7.81; 20.99) |
* p<0.001 logical regression model; ** p<0.0001
Analysis by active number of drugs in the background regimen, showed greater responses in the etravirine vs placebo arm, for suppression to both <50 and <400 copies/mL, with each number of active drugs. The differences between the two arms became smaller as the active numbers of background drugs increased. For example, in DUET 1, suppression to <50 copies/mL was achieved by 47% vs 9%, 59% vs 24%, 68% vs 61% and 66% vs 65% in the etravirine vs placebo arms, when 0, 1, 2 and > 3 other active drugs were included.
Pre-study estimated 60% patients would achieve <50 copies/mL at week 24, if they were also using T-20 for the first time, independently of whether they received placebo or active drug. Approximately 40% of patients in DUET 1, and 50% in DUET 2 in each arm used T-20. In DUET 1, 25% used T-20 as a new drug and 16% re-used T-20, and in DUET 2 the rates were 25% and 27% for new and reused T-20 respectively.
The analysis by T-20 use was more clearly presented in DUET 1, and showed the predicted lack of statistical difference in the two arms when T-20 was used as a new drug: 60% vs 56% achieving <50 copies/mL (p=0.7935) and 84% vs 70% <400 copies/mL (p=0.1218), in the etravirine vs placebo arms. In patients who were either not using T-20, or not using it as a new drug, the difference remained significant: 55% vs 33% achieving <50 copies/mL in the etravirine vs placebo arms (both P<0.0001), see Table 3.
Table 3: Virological response by use of T-20 in background regimen
| ETR | Placebo | p-value | |
|---|---|---|---|
| <50 copies/mL | |||
| T-20 as new drug | 60% | 55% | 0.7935 |
| No T-20, or T-20 reused | 56% | 33% | <0.0001 |
| <400 copies/mL | |||
| T-20 as new drug | 84% | 70% | 0.1218 |
| No T-20, or T-20 reused | 73% | 44% | <0.0001 |
Serious side effects, and side effects leading to discontinuation were comparable, including neuropsychiatric events. Rash was slightly more common in the etravirine arm but lead to discontinuation in <2% patients. No clinically relevant changes in laboratory parameters were reported.
Predicting the degree of cross-resistance between etravirine and other NNRTIs is difficult. An earlier analysis, reported in the last issue of HTB, identified that having three or more mutations from a set of 13 etravirine-associated mutations [V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S] is associated with a poor response. [3]
Comment
The DUET studies are the first trials to demonstrate a clear antiviral benefit of etravirine in treatment-experienced patients.
As with any drug in experienced patients, it is important to analyse the contributory effect of other active drugs (ie new use of T-20, darunavir, etc) in order to see the benefit from the study drug.
Presenting this data is difficult, and complicated by reliance on baseline resistance tests, which may, or may not, accurately define the numbers of sensitive drugs in the background regimen. Based on analysis of darunavir and T-20 sensitivity, in the DUET studies, patients with two other active drugs performed similarly well, whether they received placebo or etravirine. While this may be a difficult result to explain, etravirine is clearly more tolerable a choice than T-20.
A cumulative benefit of three active drugs was shown in the recent raltegravir studies, and in practice, patients with multiple drug resistance may be able to achieve higher rates of suppression with three active drugs if raltegravir is also included in the regimen.
This study was notable for including access to two investigational drugs, but was largely possible because they are both in development by the same company.
Activist pressure has long-argued for this type of design to reduce exposing multi-drug resistant patients using investigational drugs, to sequential monotherapy.
A similar model needs to be developed for access to several new agents in development when different companies are involved.
References:
- Mills A, Cahn P, Grinsztejn B et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients. 4th IAS Conference, Sydney, 2007. Abstract WESS204-1.
http://www.ias2007.org/pag/Abstracts.aspx?SID=151&AID=5515 - Katlama C, Campbell T, Clotet B et al. DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treatment-experienced HIV-1 infected patients. 4th IAS Conference, Sydney, 2007. Abs WESS204-2.
http://www.ias2007.org/pag/Abstracts.aspx?SID=151&AID=5479 - Thirteen mutations linked to resistance to etravirine (TMC125). HIV Treatment Bulletin June/July 2007.
http://www.i-base.info/htb/v8/htb8-6-7/Thirteen.html