Darunavir/Ritonavir plus TMC125 Shows Good Efficacy and Safety in Patients with Resistant HIV

The protease inhibitor (PI) darunavir (Prezista; TMC114), co-administered with 100 mg ritonavir (Norvir) and other antiretroviral agents, was recently approved by the FDA for the treatment of HIV infection in treatment-experienced adult patients, such as those with viral strains resistant to more than one other PI.

TMC125 is an experimental next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) currently being investigated in Phase III trials (DUET 1 and 2) in treatment-experienced adult patients.

Both drugs, being developed by Tibotec, Inc., have demonstrated potent antiretroviral activity in studies to date.

In the present study, presented at the 46th ICAAC in San Francisco, researchers in Belgium and the U.K. assessed Week 24 responses, pharmacokinetics, safety, and baseline phenotypic susceptibility results when the darunavir/ritonavir and TMC125 were used together.

A total of 12 multi-class-experienced patients with resistance to 3 drug classes received 600/100 mg twice-daily darunavir/ritonavir plus 200 mg once-daily TMC125 (new formulation) plus nucleoside reverse transcriptase inhibitors (NRTIs), with or without enfuvirtide (Fuzeon; T-20). Six had taken tipranavir (Aptivus) and enfuvirtide previously; only 3 used enfuvirtide for the first time.

At baseline, participants had a median CD4 cell count of 75 cells/mm3 (range 3-490) and a median HIV viral load of 4.6 log copies/mL (range 3.9-5.5). Genotypic and phenotypic resistance testing, safety, and efficacy parameters were assessed at baseline and over the study period.

Results

Of 12 total patients, 1 completed 16 weeks and 10 completed 24 weeks at the time of the analysis.

At baseline, subjects had the following numbers of resistance mutations:

- primary PI mutations: median 4 (range 0-5);
- PI resistance-associated mutations: median 11 (range 2-13);
- NRTI mutations: median 7 (range 2-9);
- NNRTI mutations: media 2 (range 0-6).

For the 11 patients with 16-24 weeks of therapy, the median fold change values ranged from 0.4 to 137.6 for all PIs and from 0.6 to 104.9 for all NNRTIs.

Viral isolates from all patients retained susceptibility to TMC125.

At week 24 (n = 10), patients achieved at least a 2.3 log (median 2.75) decrease in HIV RNA.

9 of 10 had viral loads below 40 copies/mL

The 10th patient had a detectable viral load of 722 copies/mL.

The 11th patient had a viral load below 400 copies/mL at week 16.

The median CD4 count increase was 113 cells/mm3.

No serious adverse events or changes in laboratory safety parameters were reported.

Conclusion

Based on these results, the researchers concluded, "The combination [of darunavir and TMC125] was well tolerated and showed impressive short-term efficacy against 3-class resistant HIV. Further studies of this combination are ongoing."

Chelsea and Westminster Hospital, London, U.K.; St. Mary's Hospital, London, U.K.; Tibotec BVBA, Mechelen, Belgium.

10/03/06

Reference
M Boffito, A Winston, A Jackson, and others. Week 24 Results and Baseline Phenotypic Susceptibility in Treatment Experienced Patients Initiating the Combination of TMC114/r and TMC125. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1000.

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