Background of study: TMC125 (R165335) is a novel, next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with equipotent in vitro activity  (EC₅₀ = 1-10 nM) against wild-type HIV-1 and NNRTI-resistant variants encoding L100I, K103N, Y181C, Y188L and/or G190A/S mutations.

Objective: To evaluate the antiviral activity of TMC125 in antiretroviral experienced patients infected with NNRTI-resistant virus who fail on an NNRTI-containing regimen.

Design: Open Phase IIA study. Sixteen HIV-1-infected male individuals, failing an efavirenz (EFV) or nevirapine (NVP) containing therapy and presenting with documented resistance to EFV (>10 fold change in susceptibility assessed by VirtualPhenotypeÔ and/or AntivirogramÒ), were eligible for inclusion. Patients received 900 mg TMC125 BID for 7 days, substituting the failing NNRTI, while they continued taking their NRTIs (unchanged). After day 7, treatment with TMC125 was terminated; treatment was continued with an investigator-selected ART.

Results: Sixteen patients were enrolled, with the following median baseline characteristics: age: 38 years; CD4 cell count: 389 cells/μL; HIV-1 RNA: 10,753 copies/ml. The median fold change in EC₅₀ (AntivirogramÒ) to EFV at screening was 111 (range: 16-659), while fold changes in EC₅₀ (AntivirogramÒ) to TMC125 ranged between 0.5 and 8.3 (median: 2.6). All patients had >35 fold decreased sensitivity to NVP. NNRTI mutations found included L100I, K103N, Y181C, Y188L, G190A/S, with 12 patients having multiple NNRTI mutations. All patients had NRTI mutations and all but one had protease mutations.  One patient was withdrawn on day 5 because of non-compliance.

The median (min; max) changes in log₁₀ viral load from baseline were:

Day 2	Day 4	Day 6	Day 8
-0.062* (0.2;-0.52)	-0.352* (0.2; -0.97)	-0.643* (0.09; -1.95)	-0.889* (-0.18; -1.71)

*intra-group comparisons versus baseline : p<0.001

After 7 days of treatment, the median decrease in viral load was 0.9 log₁₀ from baseline. Viral load continued to decrease on day 8. Twelve patients (75%) had a decrease in viral load of at least 0.5 log₁₀; in 7 patients (44%) a decrease greater than 1 log₁₀ was observed. There was no relationship between response and geno/phenotype.

Eleven patients reported Grade 1 adverse events. Diarrhoea (n=5), and headache (n=4) were most common.

Conclusion: TMC125, a next-generation NNRTI, administered at 900 mg BID for 7 days in treatment-experienced patients with highly NNRTI-resistant virus and currently failing on an NNRTI-containing regimen demonstrates significant antiviral potency and is well tolerated.