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03/05/2014

Nucleoside-sparing vs. Standard Nucleoside-containing Initial ART Compared: CROI 2014


All HHS guidelines prefer regimens for initiation of antiretroviral therapy (ART) that include two nucleoside (or nucleotide) analogs combined with a third agent from another antiretroviral class. Although currently recommended nucleosides are safe and well tolerated in most patients, there are lingering concerns about renal, bone, cardiovascular and metabolic safety with certain agents nucleosides. A safe and effective nucleoside-sparing regimen would be a useful addition to current ART.

Raffi and co-investigators from sites across Europe, reported results of a large randomized open-label trial designed to demonstrate the non-inferiority of a nucleoside-sparing regimen to standard, guidelines preferred ART in treatment-naive patients. All participants (n=805) received darunavir with ritonavir (800mg and 100 mg once daily) and were randomized to either raltegravir 400mg twice daily (RAL) or tenofovir DF 300mg/emtricitabine 200 mg once daily (TDF/FTC). The primary endpoint was the proportion with treatment failure, defined as viral load reduction <1 log by week 18, viral load ≥400 copies/mL at week 24 or ≥50 copies at week 32 and beyond, or occurrence of a new AIDS-defining illness or death. At week 96, treatment failure had occurred in 17.4% in the RAL arm and 14.7% in the TDF/FTC arm (difference 3.7%, 95% CI -1.1, 8.6%) which met the protocol definition of non-inferiority, which required the upper bound of the 95% CI to fall below 9.0%. An analysis including discontinuation of randomized therapy as failure also achieved non-inferiority. Subgroup analysis of the primary endpoint favored the TDF/FTC in those with CD4 counts <200/mm3 at baseline (RAL 39.0% vs. TDF/FTC 21.3%, p=0.02). For those with baseline viral load >100,000, the trend also favored TDF/FTC (p=0.09). Similar numbers had protocol-defined virologic failure, but viral loads at failure were higher in the RAL arm. Resistance mutations were rare in the RAL arm (n=5). No resistance was detected in TDF/FTC arm. Total, LDL and HDL cholesterol increased more in the RAL arm and estimated creatinine clearance decreased more in the TDF/FTC arm. These differences were statistically significant but too small to be a much clinical importance.

In this study, the nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir performed similarly to standard nucleoside containing ART. A potency difference was apparent for those with low CD4 and high viral load at baseline, and no excess of clinically important nucleoside toxicities was seen. This regimen is a reasonable alternative to standard nucleoside-based ART for patients in whom there is a reason to avoid nucleosides, especially if CD4 is above 200 and viral load below 100,000.

Reference:
Raffi F, Babiker AG, Richert L, et al. First-Line RAL + DRV/r Is Non-Inferior To TDF/FTC + DRV/r: The NEAT001/ANRS143 Randomised Trial. Abstract 84LB, CROI 2014, Boston, MA, March 3-6, 2014.


Source: Reporting for PRN News: David H Shepp, MD