SUMMARY: People with HIV strains that switch from CCR5 to CXCR4 co-receptor use during treatment with the CCR5 antagonist maraviroc (Selzentry) do not experience adverse outcomes including subsequent treatment failure or HIV disease progression, according to findings from the MERIT study presented last week at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) in Boston.

By Liz Highleyman

People with late-stage HIV disease are more likely to have CXCR4-tropic HIV -- though a recent study found that even in this group CCR5-tropic strains are most common -- and some research indicates that CXCR4-tropic strains are associated with faster disease progression.

S. Portsmouth from Pfizer and colleagues looked at long-term clinical consequences among people who experience a CCR5 to CXCR4 co-receptor tropism switch during treatment with maraviroc-containing regimens. Maraviroc prevents HIV from using the CCR5 co-receptor, so is only effective against CCR5-tropic virus.

People considering maraviroc receive a tropism test to ensure that they have exclusively CCR5-tropic HIV strains. But HIV can mutate to switch tropism, which sometimes happens in patients experiencing virological failure while taking CCR5 antagonists. This prompted concern that use of maraviroc might favor the more aggressive CXCR4-tropic strains.

Investigators conducted an analysis of 15 participants in the MERIT trial who experienced treatment failure on maraviroc and showed phenotypic evidence of co-receptor tropism change (4% of all maraviroc recipients). They looked at changes in CD4 cell count, response to subsequent therapy, and clinical events. The average duration of follow-up was 192 weeks (range 12-240 weeks).

Briefly, MERIT included more than 700 treatment-naive participants who were randomly assigned to receive either twice-daily maraviroc or once-daily efavirenz, both in combination with zidovudine/lamivudine (Combivir). As previously reported, In an analysis of patients determined to have only CCR5-tropic virus using the current more sensitive enhanced Trofile tropism test, maraviroc and efavirenz were equally effective, but maraviroc was associated with larger CD4 cell gains and fewer side effects.

Results

	Among the 15 patients with a tropism switch, the median time to emergence of CXCR4-tropic virus was 85 days (range 14-504 days).
	The median time to switching drug regimens was 183 days (range 74-548 days).
	The median CD4 cell gain at the end of follow-up was 218 cells/mm3, up from a baseline median of 220 cells/mm3.
	2 serious adverse events were observed, secondary syphilis and tuberculosis, both considered unrelated to therapy.
	Among people with available data about subsequent regimens, 5 received NNRTIs, 3 received protease inhibitors, and 1 received a triple NRTI regimen.
	All but 1 patient (who switched to a NNRTI) had suppressed viral load at week 192.
	More sensitive tropism testing showed that many of the 15 patients actually had some CXCR4-tropic, dual-tropic, or mixed HIV strains at study entry, and therefore should not have been included in MERIT:
	Enhanced Trofile would have excluded 7 participants; Deep sequencing (2% CXCR4-tropic cut-off) would have excluded 4 patients; Geno2pheno genotyping would have excluded 5 patients.
	Among participants with available follow-up tropism data after switching to a regimen without maraviroc, some reverted to CCR5-tropic strains, but some maintained CXCR-tropic virus.

"With extended follow-up, no adverse clinical consequences were observed following failure-associated emergence of CXCR4-using virus with maraviroc," the researchers concluded. "Subjects had good immunological outcomes and responded to subsequent therapy. Tropism reverted to [CCR5] in some patients after stopping maraviroc."

Investigator affiliations: Pfizer, New York, NY; Pfizer, Sandwich, UK; British Columbia Ctr for Excellence in HIV, Vancouver, Canada; Pfizer, New London, CT.

9/21/10

Reference
S Portsmouth, M Lewis, C Craig, and others. Long-Term Outcome of Individuals Experiencing an HIV-1 Co-Receptor Tropism Switch in the MERIT Study. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010.
(Abstract H-923).