Over the past few years, numerous studies have examined the use of NRTI-sparing regimens in initial therapy. These regimens generally have not been as effective as standard regimens, for reasons that are not entirely clear, or have had higher rates of toxicity. Two small studies previously examined the combination DRV/r + RAL, and showed very different efficacy results (see Dolutegravir + Raltegravir without NRTIs, Revisited). At CROI last month, researchers presented 96-week results of NEAT-001, a much larger randomized open-label comparison of RAL (BID) + DRV/r (QD) with TDF/FTC + DRV/r (all QD) in treatment-naive patients.
The two treatment groups (approximately 400 patients each) were generally well matched, with the median HIV RNA approximately 4.76 log10 and median CD4 count 333 cells/µL; by protocol, patients had no major resistance mutations at baseline.
Results at 96 weeks included the following:
|Failure (which was defined by either virologic or clinical criteria) was seen in 17.4% of the RAL + DRV/r group and 13.7% of the TDF/FTC + DRV/r group at 96 weeks, a difference that was not statistically significant. |
|HIV RNA was <50 copies/mL in 89% of the RAL + DRV/r group and 93% of the standard therapy group at 96 weeks (89% and 91%, respectively, at 48 weeks).|
|In those with baseline HIV RNA levels of >100,000 copies/mL, failure was seen in 36% of the RAL + DRV/r recipients and 27% of TDF/FTC + DRV/r recipients (this result barely missed statistical significance); in those with baseline CD4 <200 copies/µL, failure rates were 39% and 21%, respectively (statistically significant).|
|Resistance developed in patients with virologic failure in the RAL + DRV/r treatment group but not in the comparator group:
|5 of 28 evaluable genotypes in RAL + DRV/r patients showed emergent integrase mutations (1 also had a reverse transcriptase mutation). |
|No emergent resistance mutations were found in the 13 TDF/FTC + DRV/r patients with evaluable genotypes after virologic failure.|
|Mean CD4 increases were essentially the same in the two groups, 267 and 266 cells/µL.|
|There were no significant differences between treatment groups in serious adverse effects.|
|Lipids: There were greater increases in total cholesterol, LDL, and HDL in the RAL + DRV/r group; these were statistically significant but perhaps not clinically significant.|
|Renal: Creatinine clearance decreased in the TDF/FTC + DRV/r group (-3.8) and was little changed in the NRTI-sparing group (+0.9 mL/min); p = .02.|
Clinical Bottom Line
Study researchers concluded that, for first-line therapy, the NRTI-sparing combination of RAL + DRV/r was noninferior to the standard regimen of TDF/FTC + DRV/r at 96 weeks. It is important to remember, however, that patients with high pretreatment HIV RNA or low CD4 counts on the NRTI-sparing regimen had higher rates of treatment failure. Additionally, patients with virologic failure on RAL + DRV/r paid a higher cost for that failure in terms of resistance mutations. For now, RAL + DRV/r may be a viable option for certain patients (eg, those with significant contraindications to NRTIs), but for most, the standard regimens remain appropriate.
For patients who "need" NRTI-sparing regimens, future studies examining the combination of dolutegravir + DRV/r (for an entirely once-daily regimen) may be useful, as would the inclusion of 3TC, a largely "benign" NRTI, to possibly increase regimen potency without adding significant toxicity.