Background

There is a pressing need for antiretroviral (ARV) medications that are active against drug-resistant HIV. TMC114 is an investigational protease inhibitor (PI) that is used in combination with low-dose ritonavir. This randomized controlled study presents a planned 24-week interim analysis of two 96-week Phase II trials in patients with PI resistance.

Efficacy of TMC114/r in 3-Class Experienced Patients with Limited Treatment Options

Abstract: 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. Abstract 164LB. C Katlama, D Berger, N Bellos, B Grinsztejn, Richard Haubrich, T Wilkin, J M Molina, C Steinhart, R Pedro, M P de Béthune, S De Meyer, R Hoetelmans, W Parys, T Vangeneuden, and E Lefebvre.

Description: Study participants were experienced in 3 drug classes, with primary PI mutation, and HIV RNA >=1,000 copies/mL on a PI-containing regimen. They received an optimized background of 2 nucleoside analogues (NRTIs) with or without enfuvirtide (T-20), and were randomized either to 1 of 4 dosing strategies of TMC114 or to a comparator PI of choice (CPI). The primary endpoint was the decrease in HIV RNA at 24 weeks; the secondary endpoint was the proportion of patients with >=1 log₁₀ decrease in HIV RNA.

This analysis included 497 patients. Treatment groups were well matched at baseline and had a median HIV RNA of 4.5 log₁₀ copies/mL and CD4 counts of 136 cells/µL (TMC114) and 163 cells/µL (control). The subjects had extensive prior exposure to ARVs, with a median of 8 PI mutations (3 primary PI mutations); 66% had phenotypic resistance to all approved PIs, with a median phenotypic fold change of 79 for lopinavir, 38 for atazanavir, and 4 for TMC114.

Results: By intent-to-treat analysis, each of the TMC114 treatment groups achieved higher rates of viral suppression and CD4 increase than did the CPI group, with the TMC114/ritonavir 600/100 mg twice daily group showing the greatest efficacy.

All virologic results were statistically significant for the comparisons between TMC114/ritonavir groups and the comparator group (p <.001).

In subset analysis, the TMC114/ritonavir 600/100 mg group showed much higher rates of viral suppression than did CPI recipients in various subgroups, including subjects with >=3 primary PI mutations and those with baseline resistance testing that predicted no sensitivity to any ARVs in the background regimen. T-20 was used in approximately 47% of subjects in all groups. In the 600/100 mg TMC114 group, rates of viral suppression to <50 copies/mL were higher in subjects who also received T-20 (67% vs 37% of those who did not receive T-20).

Adverse effects consisted primarily of headache and gastrointestinal disturbance but occurred at the same frequency in the TMC114 groups and the CPI group. Grade 3-4 increases in total cholesterol or triglyceride levels were seen in 1-1.5% and 6-6.6%, respectively. There were no significant differences in adverse effects among TMC114 dose groups.

Comment: In a study population with extensive prior exposure to numerous ARVs and markers of significant PI resistance, therapy with TMC114 was very effective at 24 weeks, particularly if combined with T-20. TMC114 appears to be associated with a relatively low rate of adverse effects, including dyslipidemia and hepatotoxicity, and is likely to become an important agent in the treatment of patients with PI resistance. It has not yet been studied in initial therapy.

The TMC114/ritonavir 600/100 mg twice daily dosing regimen has been selected for evaluation in further clinical trials.