Unboosted twice-daily atazanavir plus raltegravir

A phase 2b comparison study compared an experimental unboosted combination of atazanavir (ATZ) 300mg plus 400mg raltegravir (RAL), both twice-daily, to boosted atazanavir/r (300/100mg) plus tenofovir/FTC, both once-daily (the SPARTAN study). The results were presented as a late breaker.

This small study randomised 94 people 2:1 to atazanavir/raltegravir (n=63) or the control group (n=31). The primary analysis at week 24 (percentage of patients with viral load < 50 copies/mL) used confirmed virologic response (CVR NC=F). The study was not powered to detect differences between the
groups.

Baseline characteristics included 90% male, 85% white, mean CD4 250 cells/mm3 and mean viral log of 4.9 logs with approximately 50% patient having viral load >100,000 copies/mL.

About 10% patients in each arm discontinued treatment, all of who were undetectable in the atazanavir/raltegravir and they remained suppressed to week 24. The raltegravir arm produced a more rapid virological response, with 75% vs 63% undetectable at week 24, with higher CD4 increases in the experimental arm +166 vs +127 cells/mm3. Viral response rates were slightly higher using less stringent analyses. Of the 11 patients with virlogical failure in the raltegravir arm (>50 copies/mL; 6/11 were >400 copies/mL), eight had baseline viral load >250,000 copies/mL. Four patients had resistance testing, with 3/4 showing integrase mutations and the fourth phenotypic resistance. In the control group there were eight failures >50 copies/mL (4/8 with baseline viral load >250,000 copies/mL) but only one at >400 copies/mL. No resistance was indentified to atazanavir in either arm.

A PK substudy showed approximately 39% increased AUC and 30% increased Cmin for atazanavir twice-daily compared to levels seen with ritonavir boosted plus tenofovir.

Side effects were broadly similar, except significantly higher bilirubin levels in the raltegravir arm (60% vs 43% grade 3/4; and 20% vs 0% grade 4). Lipid differences included higher HDL cholesterol and lower triglycerides in the raltegravir arm. LDL and total cholesterol were similar.

These differences, together with no virological benefits compared to standard of care regimens, and the twice-daily regimen, were sufficient for BMS to close the study early.

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For UK patients at least, the cost of double-dose atazanavir plus raltegravir would limit the use of this combination, even if the results had been more successful.