Data from the randomized double-blind QDMRK study of once-daily vs twice-daily dosing of raltegravir were presented at CROI. The basic findings had been announced at the end of 2010 in a press release from the manufacturer, but this was the first time the study results were made available in full.
In QDMRK, antiretroviral-naive individuals without NRTI resistance were randomized to raltegravir at a dosage of either 800 mg once daily (QD) (n = 386) or 400 mg twice daily (BID) (n = 389), along with tenofovir + emtricitabine (FTC). The groups were well matched at baseline; the geometric mean HIV RNA was about 69,000 copies/mL, with 40% having RNA levels of >100,000 copies/mL; the mean CD4 count was 285 cells/µL. At 48 weeks, HIV RNA was suppressed to <50 copies/mL in 83.2% of the QD group and 88.9% of the BID group; a similar difference between groups was seen at the <400 copies/mL threshold. By the study criteria, the QD raltegravir regimen proved to be inferior to the BID regimen. Based on these results, the study was terminated upon recommendation of the Data Monitoring Committee.
The underperformance of QD raltegravir was seen primarily in subjects with baseline HIV RNA >100,000 copies/mL; in this group, only 74% of the QD raltegravir recipients achieved HIV RNA levels of <50 copies/mL, compared with 84% of the BID recipients. Similarly, in those with low CD4 counts at baseline (≤200 cells/µL), the rate of virologic suppression was lower in the QD group (71% and 81%, respectively). In subjects with baseline HIV RNA levels of <100,000 copies/mL, the QD raltegravir regimen approached, but did not match, the virologic efficacy of BID raltegravir (89.1% vs 91.9%, respectively).
There were no significant differences in adverse events between treatment groups. Pharmacokinetic evaluations showed that raltegravir trough concentrations were substantially lower (5-6 times) in the QD arm compared with the BID arm, suggesting at least a partial explanation for the study findings. Among subjects with confirmed virologic failure for whom resistance testing could be done, virus in 9 of 27 QD subjects had mutations associated with resistance to both raltegravir and FTC, whereas 11 had FTC resistance alone. In the BID arm, a lower proportion had resistance: 2 of 12 subjects had raltegravir + FTC resistance mutations, and 4 had FTC resistance alone.
Clinical Bottom Line
In subjects with baseline HIV RNA levels of >100,000 copies/mL, QD raltegravir + tenofovir/emtricitabine clearly yielded inferior virologic results, and high rates of emergent integrase inhibitor resistance. In subjects with lower viral loads, the difference in virologic failure rates of the two treatment groups was not statistically significant, although the QD group had a slightly lower rate of virologic suppression (a small numeric difference favoring BID raltegravir was seen in each comparison shown [eg, time to loss of virologic response and virologic failure rates in lower as well as in higher HIV RNA strata], a point emphasized by the presenter). It is not known whether there are subsets of patients for whom QD raltegravir may be a viable option (eg, those with low baseline viral loads, and those with stable virologic suppression who request regimen simplification), but QD raltegravir should be considered cautiously, and on an individual basis.
On the other hand, this study showed that recipients of BID raltegravir + tenofovir/emtricitabine had extremely high rates of virologic suppression, including persons with high baseline HIV RNA viral load; this regimen is confirmed as an effective and tolerable option for initial antiretroviral therapy.