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Title: Pharmacokinetics and Antiretroviral Response Show Promise With Combination of 2 New Drugs in Patients With High-Level Viral Resistance: Presented at BHIVA

"Pharmacokinetics and Antiretroviral Response Show Promise With Combination of 2 New Drugs in Patients With High-Level Viral Resistance: Presented at BHIVA"

By Ted Bosworth BRIGHTON, UK -- April 5, 2006 -- A pilot study testing a combination of 2 new HIV drugs for advanced HIV has suggested that they are compatible and may provide increased likelihood of durable HIV suppression if used together. The study drugs were the ritonavir-boosted protease inhibitor (PI) TMC114/r and the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125. Several previous trials have suggested that the likelihood of a virologic response in heavily pretreated patients is substantially increased when 2 agents with predicted efficacy are started at the same time, said study presenter Akil Jackson, MD, physician, Chelsea and Westminster Hospital, London, United Kingdom. "The combination was well tolerated and showed impressive short-term efficacy against 3-class resistant HIV," Dr. Jackson reported. "Studies of this combination are warranted." In this study, presented here on April 1[^st at the 12^th Annual Conference of the British HIV Association (BHIVA), Dr. Jackson and coinvestigators enrolled 10 patients with documented resistance to at least 3 classes of antiretroviral drugs.

Patients' median CD4 count at baseline was 75 cells/mm³, median baseline viral load was 4.6 log10 copies/mL, median number of primary PI mutations was 4. These patients had a median of 2 NNRTI resistance mutations and a median of 6 mutations to nucleoside reverse transcriptase inhibitors (NRTIs).

The goal of the study was to evaluate the pharmacokinetics (PK) as well as the safety and efficacy of a combination of TMC114/r and TMC125. All patients received TMC114/r in a dose of 600/100 mg and TMC125 in a dose of 200 mg. The drugs were combined with at least 2 NRTIs with or without enfuvirtide.

Analyses of PK were conducted on day 28 and the safety and efficacy analyses were conducted over 12 weeks.

TMC114/r exposure was unchanged in the presence of TMC125 relative to PK patterns observed with TMC114/r in the absence of this NNRTI. TMC125 exposure in the presence of TMC114/r was reduced by 30%, but plasma levels remained above predicted minimum inhibitory concentrations.

The antiretroviral effects of the combination were potent, Dr. Jackson said. At 12 weeks median viral load was reduced by 2.76 log10 copies/mL, and all patients achieved at least a reduction of 2-log10 copies/mL. In addition, all patients achieved a viral load < 400 copies/mL, and 8 of the 10 achieved a viral load < 40 copies/mL. There was a median increase of 87 CD4 cells/mm³ over the course of the 12-week study.

No safety issues were identified in this small series, Dr. Jackson noted. There were no serious adverse events or major laboratory abnormalities observed.

These data are encouraging because "combinations of investigational agents may represent the only therapeutic option" in highly treatment-experienced patients with resistance to multiple antiretroviral drug classes, Dr. Jackson said.

On the basis of this study's findings, he indicated that a regimen that includes both TMC114/r and TMC125 may be an option in this population. Larger confirmatory studies are needed, he added.

[Presentation title: Pharmacokinetics and Antiretroviral Response to TMC114/r and TMC125 Combination in Patients With High-Level Viral Resistance. Abstract O10]

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