15th HIV Resistance Workshop: can new Tibotec NNRTI overcome cross-class resistance?

TMC 125, yet another contribution from Tibotec’s arsenal of new antiretrovirals is a non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in Phase II/III development. TMC 125’s considerable appeal is its potential for activity against HIV resistant to existing NNRTIs, in particular, the impact of K103N and Y181C conferring high-level resistance to efavirenz (EFV) and nevirapine (NVP). In a Phase IIb study responses were observed to patients receiving TMC 125 800mg twice daily (BID) at 24 weeks,

At baseline, 29 of the 79 patients had both K103N and Y181C; always observed in combination with 1-4 other NNRTI mutations.

The authors noted that responses were adjusted for baseline viral load, CD4 and enfuvirtide, the latter proving to be a significant factor in improved response.

Two observations are of note from this study; the presence of K103N at baseline appears to have little impact on viral response, but the absence of the Y181C mutation at baseline does seem to reflect a more pronounced positive response to TMC125 with nearly 0.6 log enhancement in virologic response. Whether these findings prove to be significant in the clinic remains to be seen. Certainly with the ubiquity of EFV use in many European countries, the response to K103N is promising, but enthusiasm is likely to be tempered by the less robust response to Y181C-containing viral strains which many patients in long-term salvage are likely to harbour.

Joe Eron from the University of North Carolina commented that contrary to the existing belief that NNRTIs are structurally aligned with similar impact on genetic barrier and resistance, perhaps these findings suggest that EFV and NVP may not be so similar after all. Dr Eron further suggested that patients may have longer-term experience of NVP given its earlier introduction to clinical practice; perhaps these patients had been on a NVP-failing regimen for longer.

This may have implications for TMC 125 use in developing nations that have a long history of NVP use as a result of adhering to WHO guidelines for first-line therapy. Dr Eron asked Tibotec if results from the study had been stratified according to patients’ experience of EFV or NVP. Tibotec confirmed this but were unable to present the subsequent breakdown at the meeting.