July 27, 2005
The novel protease inhibitor (PI) TMC114 has aroused considerable attention since it began early-stage clinical trials several years ago. At recent conferences, the potency of this molecule in phase 2 clinical trials as an antagonist of HIV replication has been documented.1-3 The current study was designed to assess how ritonavir (RTV, Norvir)-boosted TMC114 compares with other currently approved PIs in patients previously exposed to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and PIs.
This was a multi-centered, phase 2B efficacy and safety trial led by Christine Katlama, of Hôpital Pitié-Salpêtrière in Paris, France, and colleagues. A total of 318 patients were enrolled. All were currently on stable, PI-based antiretroviral therapy, had a viral load greater than 1,000 copies/mL and had at least 1 primary mutation associated with resistance to PIs. (On average, each patient had previously received 4 different PIs.) At the time of entry, the mean viral load was 4.48 log copies/mL and the average CD4+ cell count was 179 cells/mm3.
Study patients were randomized to 1 of 2 arms. In the first, patients received 1 of 4 different TMC114 + ritonavir doses: 400 mg/100 mg once daily, 400 mg/100 mg twice daily, 600 mg/100 mg twice daily or 800 mg/100 mg once daily. In the second (control) arm, patients received different PIs that had been selected by the clinical investigators. All patients received an optimized background regimen of 2 NRTIs in addition to the selected PI, and were also able to receive enfuvirtide (T-20, Fuzeon).
The 24-week results showed that TMC114 + ritonavir was very well tolerated; only 10% of the 255 patients receiving this drug discontinued therapy, versus 62% of the 63 control patients, with most discontinuations due to virologic failure.
Key 24-week efficacy data is noted in the chart below, in which the most effective TMC114 + ritonavir dose of 600 mg/100 mg twice daily is compared to the control arm, using an intent-to-treat analysis.
|TMC114 600 mg + Ritonavir 100 mg||Control Arm|
|Mean CD4+ cell count increase||124 cells/mm3||20 cells/mm3|
|% of patients with >1 log viral load reduction||77%||25%|
|Mean viral load decline||2.03 log10 copies/mL||0.63 log10 copies/mL|
|% of patients achieving viral load <50 copies/mL||53%||18%|
Reductions to less than 50 copies/mL in viral load were seen in 63% of the 19 individuals who received enfuvirtide as well as TMC114 + ritonavir, compared to 56% of individuals who received TMC114 + ritonavir in the absence of enfuvirtide. This was not a statistically significant difference.
These results document the ability of TMC114 + ritonavir to profoundly impact viral load in treatment-experienced individuals whose virus contains primary mutations associated with resistance to currently approved PIs and who had previously failed PI-containing regimens.
Importantly, the benefits of TMC114 + ritonavir did not seem to be particularly dependent on co-administered enfuvirtide in this study. This trial and others like it strongly suggest that TMC114 will be a potent, well-tolerated addition to our armamentarium of PI compounds. Expectations are that it will be effective in individuals who have previously failed PI-containing regimens, and that it will also be an extremely potent drug in patients receiving it as part of first-line therapy.
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