 |
|
|
| |
Etravirine With 300/100 or 400/100 mg of
ATV/r in Treatment-Experienced People
|
| |
| |
Early virologic response was reasonable in a small trial comparing 300/100 mg of atazanavir/ritonavir once daily with 400/100 mg of the protease inhibitors (PIs) plus the nonnucleoside etravirine and one nucleoside in antiretroviral-experienced people [1]. The higher atazanavir dose did not substantially raise atazanavir exposure, but it lowered etravirine concentrations.
US and Canadian regulators advise against giving atazanavir/ritonavir with etravirine. Researchers from Janssen, maker of etravirine, planned this study in part to address that contraindication.
A previous study in HIV-negative volunteers found that atazanavir/ritonavir at the standard 300/100-mg once daily dose plus 800 mg of etravirine twice daily (in the phase 2 trial formulation) yielded a 14% lower atazanavir 24-hour area under the concentration-time curve (AUC) and a 38% lower atazanavir minimum concentration (Cmin). Combining the PIs and etravirine in that study resulted in a 1.3-fold higher etravirine AUC and a 1.26-fold higher etravirine Cmin.
TEACH, a randomized, open-label, 48-week trial, is exploring two doses of atazanavir/ritonavir plus etravirine and one nucleoside in treatment-experienced people [2]. Study participants must have a viral load above 500 copies after taking at least one antiretroviral regimen but no more than two PI-based combinations. They must have virus susceptible to atazanavir, etravirine, and at least one nucleoside. All study participants started 300/100 mg of atazanavir/ritonavir once daily plus two nucleosides, excluding tenofovir because it lowers atazanavir and etravirine exposure.
After 2 weeks TEACH investigators randomized participants to maintain the 300/100-mg dose of atazanavir/ritonavir or to switch to 400/100 mg. At that point everyone substituted 200 mg of etravirine twice daily for one of their nucleosides. The researchers collected 24-hour blood samples 1 day before randomization and 14 days afterwards.
The trial randomized 22 people to each study arm. Twenty-five study participants (57%) were women, 28 (64%) were black, 8 (18%) were Asian, and 7 (16%) were white. Median initial CD4 count and viral load stood at 223 and 4.1 log10 copies/mL (about 12,500 copies). Study participants had used a median of 3 antiretrovirals (range 3 to 11).
At the 12-week point, 13 people in each arm (59%) had a viral load below 50 copies, and the average CD4 count rose by 51 cells (more with 400 than 300 mg of atazanavir). During the randomized phase of the trial, 3 people in the 300-mg atazanavir arm and 1 in the 400-mg atazanavir arm had a serious adverse event. Five people in the 300-mg group and 3 in the 400-mg group had a grade 3 or 4 adverse event. Adverse events led to treatment discontinuation in 2 people in the 300-mg group and 1 in the 400-mg group. Respective numbers of adverse events judged at least possibly related to etravirine were 5 and 4.
Adding etravirine marginally lowered the Cmin of atazanavir taken at 300 or 400 mg with ritonavir (least square mean [LSM] ratio and 90% confidence interval [CI] 0.82 (0.55-1.22) with 300 mg and 0.91 (0.63-1.33) with 400 mg). The impact of etravirine on atazanavir 24-hour AUC and Cmax was even more modest.
Janssen investigators noted that the impact of etravirine on ritonavir-boosted atazanavir "was similar [to] or less than that reported in healthy volunteers." Pushing the atazanavir dose from 300 to 400 mg yielded a less than proportional increase in atazanavir exposure.
Compared with historical controls in the DUET trial, atazanavir/ritonavir at 300/100 mg slightly raised etravirine concentrations (LSM ratio 1.07, 90% CI 0.60-1.90, for Cmin; 1.06, 90% CI 0.78-1.46, for Cmax; 1.24, 90% CI 0.88-1.76, for 12-hour AUC). At the 400/100-mg dose, atazanavir/ritonavir slightly lowered etravirine concentrations (LSM ratio 0.83, 90% CI 0.54-1.29, for Cmin; 0.87, 90% CI 0.65-1.18, for Cmax; 0.84, 90% CI 0.60-1.18, for 12-hour AUC).
The researchers rated these effects "significantly less than what was expected based on healthy volunteer data." At the 300/100-mg dose, the impact of atazanavir/ritonavir on etravirine was similar to that seen with 600/100 mg of darunavir/ritonavir twice daily in the DUET trial. Raising the dose to 400/100 mg further decreased etravirine exposure.
The TEACH team concluded that raising the atazanavir dose from 300/100 mg to 400/100 mg once daily did not boost atazanavir concentrations proportionately but did lower etravirine levels. They did not propose mechanisms that may explain these unexpected findings. This ongoing 48-week trial will continue to assess the antiviral activity, safety, tolerability, and pharmacokinetics of the combination [2].
References
1. Kakuda TN, Nijs S, Latham J, et al. Pharmacokinetics of atazanavir/ritonavir 300/100mg or 400/100mg qd when co-administered with etravirine 200 mg bid in HIV-infected patients. 13th International Workshop on Clinical Pharmacology of HIV Therapy, April 16-18, 2012, Barcelona. Abstract O_24.
2. ClinicalTrials.gov. TMC125-TiDP2-C238: an exploratory pharmacokinetics, safety and anti-HIV activity study of etravirine (ETR) when given with boosted atazanavir (ATV/RTV) at two different doses and 1 nucleoside reverse transcriptase inhibitor (NRTI) in treatment experienced HIV patients.http://www.clinicaltrials.gov/ct2/show/NCT00896051
|
| |
|
|
|
|
|
