TMC-125 and darunavir show strong effect in highly treatment-experienced, even without T-20

Study design

The two studies, DUET 1 and DUET 2, recruited patients with resistance to NNRTIs and at least three primary protease inhibitor mutations. This group of patients are the hardest to treat since they have a very limited range of drug options.

Recent studies of new drug classes have shown that patients in this category typically need a completely new class of drug – either a fusion inhibitor, a chemokine antagonist or an integrase inhibitor – in order to achieve an undetectable viral load.

However, the results of the DUET 1 and 2 studies suggest that many patients in this category can achieve an undetectable viral load without a new class of drug if they receive both etravirine and darunavir/ritonavir, and have only a modest level of NNRTI resistance.

DUET 1 and 2 are studies of identical design, carried out as phase III studies in order to obtain marketing approval for etravirine. Pharmaceutical companies normally need to present evidence from two large randomised studies to obtain marketing approval.

The studies recruited patients with confirmed resistance to NNRTIs who had detectable viral load (above 5,000 copies/ml) on their current treatment regimen, and who had at least three primary protease inhibitor mutations.

Participants were randomised to receive etravirine twice daily at a dose of 200mg or a placebo, and all participants received darunavir/ritonavir (600/100mg) and nucleoside analogues chosen after resistance testing.

A combination of the new non-nucleoside reverse transcriptase inhibitor etravirine (TMC125) together with darunavir (Prezista) boosted with ritonavir is significantly more effective than darunavir/ritonavir alone in highly treatment-experienced patients with resistance to both NNRTIs and protease inhibitors, two studies report in this week’s edition of The Lancet.

However the studies also found that in highly treatment-experienced patients new to enfuvirtide (T-20), etravirine did not provide any extra benefit if the patients also started enfuvirtide, which is from a completely new drug class, when they entered the trial. Conversely, in patients who took TMC-125 without enfuvirtide, 55 - 58% achieved viral load below 50 copies by week 24, compared with one-third in the placebo group.

Only in patients with some degree of resistance to darunavir did etravirine shine when enfuvirtide was introduced as a new drug in the background regimen: among those with moderate darunavir resistance, etravirine recipients who also took enfuvirtide for the first time were twice as likely to achieve viral load below 50 copies/ml.

Taken together these findings suggest that etravirine may prove a useful alternative to enfuvirtide in protease inhibitor-experienced patients still sensitive to darunavir, and that it will also provide useful back-up to an agent from a new class in circumstances where resistance to darunavir is growing, but there is still some sensitivity to NNRTIs.

Patient characteristics

The primary endpoint of the study was the proportion of patients with viral load below 50 copies at week 24.

Week 24 results

The use of enfuvirtide (T-20) in patients with some degree of resistance to darunavir improved the chances of achieving undetectable viral load by week 24. However, the addition of etravirine to the regimen in patients naïve to enfuvirtide who included enfuvirtide in the background regimen did not significantly improve responses.

The study reports lump together patients who were not taking enfuvirtide at all in the study and those who were `re-using` it – probably often continuing to take it because it was thought still to be partially effective – because enfuvirtide was not thought to be conferring any additional antiviral benefit in these patients.

Response according to enfuvirtide use (proportions with viral load below 50 copies/ml)

Prior NNRTI experience

Etravirine proved to be highly active in patients with one or two NNRTI-associated mutations, with just over 77% of patients in DUET 2 who did not receive or who re-used enfuvirtide achieving viral load below 50 copies/ml if they had one NNRTI mutation, 64% if they had two. In comparison 45% and 38% of the placebo group respectively achieved viral load below 50 copies/ml. A similar analysis was not reported for DUET 1.

A preliminary analysis of the DUET trials, presented last month at the HIV Resistance Workshop in Barbados, suggests that three mutations from the group V90I, A98G, L100I, L101G/P, V106I, V179A/P, T181C/I/V and G190A/S are needed in order to reduce the virological response to etravirine.

Of particular note, the K103N mutation typically selected after the failure of efavirenz does not contribute to high-level etravirine resistance.

A previous phase IIa study, TMC – C227, suggested that etravirine is unlikely to be active in patients who have been left a long time on a failing NNRTI-based regimen, since those are the patients most likely to have accumulated a larger number of NNRTI-associated mutations. In that study etravirine was not given alongside a protease inhibitor, and patients had also accumulated considerable resistance to nucleoside analogues, weakening the effectiveness of the nucleoside analogue backbone used with etravirine.

Virologic response according to baseline darunavir susceptibility and enfuvirtide use

In an accompanying editorial Professor Bernard Hirschel and Thomas Perneger of Geneva University Hospital criticise the authors and publisher of the study for not presenting a pooled analysis of the data, particularly with respect to the occurrence of opportunistic infections and death.

“A pooled analysis of clinical events, with 22 out of 599 patients on etravirine (3.7%) and 41 of 604 patients in the control group (6.8%) shows a statistically significant difference by our calculation, “they write. “People care whether they get sick or die, and rather less whether their laboratory results are normal. A combined analysis would have allowed the investigators to claim …a clinically important benefit for etravirine.”

“Furthermore a pooled analysis would have more clearly established that the efficacy of etravirine, in terms of viral load, differs by enfuvirtide status. Results of both studies suggested that etravirine benefited only patients who did not use or reused enfuvirtide. In new users of enfuvirtide, etravirine failed to confer any additional benefit. A pooled analysis would have established that etravirine is significantly more effective in the absence of new treatment with enfuvirtide (odds ratio of viral load >50 copies/ml, 0.39, 95% CI 0.30 – 0.51) than in its presence (O.81, 0.51-1.30, p=0.008).”

Adverse events

There was no significant difference in serious adverse events between the etravirine and placebo groups, although rash, generally mild to moderate, was more common in patients who received etravirine (20% vs 10% in DUET 1, 14% vs 9% in DUET 2). Thirteen patients taking etravirine discontinued the drug due to grade 3 rash, as required in the trial protocol. Rash typically emerged after about ten days on treatment and lasted for a median of twelve days.

TMC-125 had no observable effects on lipids or liver enzymes.