Once-a-day etravirine should work as first-line treatment

Once-a-day dosing of the newly-licensed non-nucleoside (NNRTI) drug etravirine (TMC125, Intelence) should be sufficient to suppress HIV in patients without NNRTI resistance, the Ninth Congress on Drug Therapy in HIV Infection heard last week. The current approved dose of the drug is two 100mg tablets taken twice a day.

Thomas Kakuda of Tibotec, the manufacturer of etravirine, told the conference that the average minimum level of etravirine seen in the blood of HIV-positive trial subjects who took the drug once daily was 58 to 59 times the level needed to inhibit 50% of HIV replication (the IC₅₀). It appeared to work just as well against non-resistant HIV as twice-daily dosing, but larger clinical studies would be needed before a once-daily dose could be recommended.

Etravirine is a candidate for once-daily (QD) dosing because it has a 'terminal half-life' of 30-40 hours, Kakuda said; that is, it takes 30-40 hours for half the drug to be eliminated from the body. In previous studies in HIV-negative volunteers, the total amount of drug exposure to the body (the 'area under the curve' or AUC) was similar in once- and twice-daily dosing.

When dosed once daily, the maximum drug level observed was 44% higher and the minimum, or trough level, was 25% lower than during twice-daily (bid) dosing. As etravirine is designed to overcome moderate levels of NNRTI resistance, a trough level 25% lower than that achieved with twice-daily dosing should be more than enough to suppress non-resistant virus.

The present study was also designed to measure levels of once-daily etravirine combined with Tibotec's protease inhibitor darunavir (Prezista); this is because darunavir reduces levels of etravirine in the blood by 37%.

Twenty-three patients with HIV who had never taken antiretrovirals before and who had no NNRTI resistance were given QD etravirine plus tenofovir/FTC (Truvada) for 14 days. Then once-daily darunavir-plus-ritonavir (DRV/r) was added for 14 days; finally the etravirine was stopped and patients continued on DRV/r plus Truvada.

Twenty of the patients were men and the group was quite evenly split ethnically (nine white, nine black and five Hispanic). Their mean age was 36 and their mean viral load was 16,000 copies/ml.

Etravirine levels in the blood were measured at day 14. At this point the average minimum etravirine blood level was 233 nanograms (billionths of a gram) per millilitre (ng/ml). This compares with 298 ng/ml observed in twice-daily dosing in the DUET study, which combined twice-daily etravirine with darunavir. The AUC was 10,410 ng/ml per hour, roughly twice the 5079 ng/ml/h observed in the DUET study, and what would be expected when twice as much drug is given half as often.

Drug levels were measured again at day 28 after the addition of DRV/r. There was virtually no change in etravirine levels, with a minimum of 236 ng/ml and an AUC of 10,720 ng/ml/h. Darunavir levels were about 20% higher than those observed in other studies without etravirine.

The patients' viral loads went down by 1.5 logs (about 30-fold) in the first 14 days on etravirine/Truvada and was down by 2 logs (100-fold) by day 28 after DRV/r was added. Patients gained an average 56 CD4 cells/mm³. There were no serious drug side-effects or discontinuations; four patients developed a rash, two attributable to etravirine and two to darunavir.

"Once-daily etravirine shows good activity at least in antiretroviral-naïve patients", commented Kakuda. "This pharmacokinetic [drug absorption] data supports further clinical investigation of once-daily dosing."

Tibotec’s study could open the way to a compact, once-daily nucleoside-sparing regimen for first-line treatment, although such an approach will need investigation of both once-daily etravirine dosing and of once-daily NRTI-sparing treatment with this combination.