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.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|
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