SUMMARY: High baseline viral load and less-than-optimal adherence help explain the higher rate of virological failure among people taking Tibotec's experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (TMC278) in a pair of recent clinical trials, according to findings presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) last week in Boston. Rilpivirine recipients were less likely than efavirenz recipients to stop treatment due to side effects, but more likely to develop drug-resistance mutations.

By Liz Highleyman

	As previously reported, in an intent-to-treat analysis at 48 weeks, 84% of participants taking rilpivirine and 82% taking efavirenz achieved viral load < 50 copies/mL overall, not a significant difference.
	Treatment response rates were higher among people with low viral load in both arms, but this effect was greater in the rilpivirine arm compared with the efavirenz arm:
	Low baseline viral load (< 100,00 copies/mL): response rates of 90% vs 84%. respectively. High viral load (> 100,000 copies/mL): 77% vs and 81%, respectively.
	10% of rilpivirine recipients and 6% of efavirenz recipients met the definitions of virological failure, a significant difference.
	Suboptimal adherence predicted virological failure in both groups, but this too had a greater effect in the rilpivirine arm.
	Viral load and adherence had a combined effect, such that people with both high viral load and suboptimal adherence were about 3 times more likely to experience virological failure in the rilpivirine arm than in the efavirenz arm.
	Among participants with virological failure, 62 (86%) and 28 (72%), respectively, had successful resistance tests.
	63% of patients with virological failure in the rilpivirine arm had genotypic evidence of new NNRTI resistance-associated mutations, compared with 54% in the efavirenz arm, which did not reach statistical significance.
	68% and 32%, respectively, developed new IAS-USA NRTI resistance-associated mutations, a significant difference.
	The 3 most common emerging resistance-associated mutations in the rilpivirine arm were M184I (n = 29), E138K (n = 28) and M184V (n = 14), with M184I and E138K usually occurring together.
	K103N was the most common resistance mutation in the efavirenz arm (n = 11).
	50% of rilpivirine recipients and 43% of efavirenz recipients with virological failure showed phenotypic resistance to their NNRTI, or evidence that the drug did not work against virus in laboratory tests.
	Fewer people in the rilpivirine arm (3%) stopped therapy early due to adverse events compared with the efavirenz arm (8%).

"These results confirm that TMC278 [rilpivirine], in combination with a [NRTI] background regimen, was effective and non inferior to efavirenz," the researchers concluded. "Virological failure was more common in patients with suboptimal adherence and/or high viral load and this effect was more apparent with TMC278 than with efavirenz."

Tibotec has submitted a New Drug Application for rilpivirine to the U.S. Food and Drug Administration (FDA) and has requested European Medicines Agency approval for rilpivirine alone and (in conjunction with Gilead Sciences) for a single-tablet regimen containing rilpivirine plus tenofovir/emtricitabine.

Investigator affiliations: Tibotec, Mechelen, Belgium; University of North Carolina, Chapel Hill, NC; irsiCaixa Foundation, Barcelona, Spain; Tibotec, Titusville, NJ.

9/24/10

Reference
L Rimsky, J Eron, B Clotet, and others. Characterization of the Resistance Profile of TMC278: 48-week Analysis of the Phase 3 Studies ECHO and THRIVE. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. (Abstract H-1810).