A number of studies in recent years have evaluated ARV combinations that avoid NRTIs. Most of these have consisted of a boosted PI with either an NNRTI or an integrase inhibitor (dual therapy), or a boosted PI alone (monotherapy). These combinations have shown variable results but generally have not been as effective as standard initial regimens. Nevertheless, it was reasonable to expect that the combination of ritonavir-boosted darunavir plus raltegravir, two very potent and well tolerated ARVs, would be highly effective. At the 18th Conference on Retroviruses and Opportunistic Infections in Boston, however, researchers presented surprising and disappointing efficacy data from a small noncomparative AIDS Clinical Trials Group (ACTG) evaluation of this regimen.(1)
At baseline, the 112 treatment-naive subjects had a median HIV RNA level of 4.9 log10 copies/mL (44% >100,000 copies/mL) and median CD4 count of 271 cells/µL, and they had no darunavir or raltegravir resistance-associated mutations. They took darunavir/ritonavir (800/100 mg once daily) plus raltegravir (400 mg twice daily), with high reported levels of adherence and few significant adverse effects. At week 24 and week 48, only 79% and 71%, respectively, had HIV RNA levels of <50 copies/mL. By week 48, a total of 28 subjects had confirmed virologic failure (11 did not achieve virologic suppression, 17 had virologic rebound after initial suppression). Integrase resistance was found in 5 of 25 subjects in whom resistance testing was done, with mutations at position N155 in all 5 subjects, and at Q148 in 2 subjects. No darunavir-associated mutations were detected. Virologic failure was associated with higher baseline HIV RNA (odds ratio for RNA >100,000 copies/mL: 3.76) and with lower CD4 counts. Additionally, all those with emergent integrase resistance had HIV RNA of >100,000 copies/mL at baseline.
Clinical Bottom Line
The virologic failure rate of darunavir/ritonavir + raltegravir in this study was substantial, and significantly higher than that reported in studies of either agent combined with NRTIs.(2,3,4) This finding was not explained by poor adherence, adverse effects, or previously described drug interactions. Pharmacokinetic data, which were collected but not presented at the conference, may yet help to elucidate this issue. It is not clear why this combination of ARVs performed so poorly, but clearly it should not be used as a stand-alone regimen, particularly for patients with high baseline viral loads. Meanwhile, NRTI-sparing strategies should continue to be approached with caution, pending the emergence of study results that demonstrate efficacy of specific combinations.
1. Taiwo B, Zheng S, Gallien S, et al; ACTG A5262 Team. Results from a single-arm study of DRV/r + RAL in treatment-naive HIV-1-infected patients (ACTG A5262). In: Programs and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 551.
2. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008 Jul 31;22(12):1389-97.
3. Lennox JL, DeJesus E, Lazzarin A, et al; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806.
4. Eron J, Rockstroh J, Reynes J, et al; QDMRK Study Team. QDMRK, a Phase III study of the safety and efficacy of once daily vs twice daily RAL in combination therapy for treatment-naive HIV-infected patients. In: Program and Abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 150LB.