Etravirine is an experimental anti-HIV drug, which is also known as TMC125. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which acts by inhibiting HIV’s reverse transcriptase enzyme. However, it is designed to work against HIV that is resistant to the currently available NNRTIs, potentially becoming the first NNRTI for use in second-line therapy after failure of efavirenz (Sustiva) or nevirapine (Viramune)^[1].

Currently, developing resistance to one NNRTI leads to resistance to all drugs in the class, and can arise after the development of only one mutation in HIV’s gene for reverse transcriptase. Etravirine was specifically designed to be less susceptible than other NNRTIs to resistance mutations. As a flexible molecule, it can change its shape to continue to bind to the reverse transcriptase enzyme that has become resistant to other NNRTIs after changing its shape. Etravirine can therefore remain active against HIV that is resistant to other NNRTIs^[2].

Etravirine is being developed by Tibotec / Virco.

Effectiveness

Several small dosing and efficacy studies have shown that etravirine can reduce viral loads after just one week of treatment. For example, a placebo-controlled phase IIA study tested the antiviral effect of 900mg etravirine dosed twice a day. After one week of treatment in twelve patients, average viral load fell by 2 log₁₀, and ten patients achieved viral loads below 400 copies/ml. No resistance was seen to develop after seven days of monotherapy, and there were no serious side-effects^[3].

Etravirine also appears to be effective in people with resistance to NNRTIs, according to a study of 16 people. Seven days after substituting etravirine for the failing NNRTI, viral load fell by an average of 0.9 log₁₀, despite resistance to efavirenz and nevirapine^[4]. There was no relationship between response and genotypic or phenotypic resistance, or between drug concentration and treatment response.

Recent studies have confirmed the safety and effectiveness of etravirine in NNRTI-resistant patients, with a dose of 800mg twice a day being selected for future studies^[5][6]. However, despite its impressive activity against NNRTI-resistant HIV, the latest findings have shown that the more NNRTI resistance mutations a patient has, the lower the viral load reduction. Patients with no NNRTI resistance mutations in their HIV had a median viral load reduction of 1.82 log₁₀ after 24 weeks of treatment with 800mg etravirine twice a day, when combined with an optimised background regimen. In contrast, those with three or more NNRTI mutations had a viral load reduction of 0.66 log_10^[7].

In a separate study in treatment-naive patients, a team from the University of Amsterdam reported that etravirine alone appears to be just as potent as a combination of AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir), abacavir (Ziagen), indinavir (Crixivan) and nevirapine. Viral load in the etravirine group fell by 1.92 log₁₀ in the first seven days of treatment, compared to 1.55 log₁₀ in the five-drug group^[8].

Despite these promising findings, one phase II trial of etravirine was stopped early after patients taking etravirine had worse outcomes than a comparator group taking protease inhibitor-based treatment. This trial included patients with experience of NNRTIs. Nevertheless, Tibotec has initiated two large phase III trials using a different formulation of etravirine. Called DUET 1 and DUET 2, these trials will assess the effectiveness of etravirine in combination with Tibotec’s new protease inhibitor darunavir (Prezista).

Side-effects

To date, the most frequent side-effects of etravirine are dizziness, headache, blurred vision, mild diarrhoea, flatulence and mild rash, all of which seem to resolve within a few days. Rash appears to be related to the maximum concentration of the drug.

The maximum tolerated dose has not yet been determined, since no serious adverse events have been reported in studies.

Resistance

Attempts to select virus with resistance to etravirine in the test tube have resulted in significantly slower emergence of drug resistance when compared with virus exposed to nevirapine or efavirenz^[9]. Mutations L100I, V179F, Y181C, G190E, L214F, M230L and Y318F are associated with etravirine resistance, although, in contrast to other NNRTIs, more than one resistance mutation needs to develop, in order to bring about resistance to etravirine^[10][11]. However, a recent study has found that Y181C may have a more pronounced impact on responses to etravirine than other mutations, such as K103N^[12].

Drug interactions

Interactions with protease inhibitors make combinations involving etravirine complicated. This is an especially important issue for a second-line NNRTI that may be used in salvage regimens with protease inhibitors. For example, etravirine blood levels decrease by 45% when taken with ritonavir (Norvir), and increase by 45 and 17% when co-prescribed with indinavir and lopinavir, respectively. Etravirine reduces saquinavir (Invirase) levels by 40% and indinavir levels by 50%.