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.

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.

Footnotes

1. Katlama C, Berger D, Bellos N, et al. Efficacy of TMC114/r in 3-class experienced patients with limited treatment options: 24-week planned interim analysis of 2 96-week multinational dose-finding trials. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Mass. Abstract 164LB.

2. Peeters M, Van Baelen B, De Meyer S, et al. TMC114/RTV activity in multiple PI-experienced patients: correlation of baseline genotype, phenotype, pharmacokinetics, and IQ with antiviral activity at day 14. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif. Abstract 533.

3. Arasteh K, Clumeck N, Pozniak A, et al. Antiretroviral activity, safety and pharmacokinetics of TMC114, a next-generation HIV-1 protease inhibitor (PI), in multiple PI-experienced patients. In: Program and abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract LB16.