First-Line Therapy: Raltegravir, Darunavir, or Atazanavir?

ACTG 5257 is a randomized open-label comparison of 3 ARV regimens for initial therapy: atazanavir + ritonavir (ATV/r), darunavir + ritonavir (DRV/r), or raltegravir (RAL), each in combination with fixed-dose tenofovir/emtricitabine.

The 3 treatment groups (roughly 600 subjects each) were well matched for baseline characteristics and were more a diverse population than most: 24% were women, 42% were non-Hispanic black, and 22% were Hispanic. Median baseline HIV RNA was 4.6 log10 copies/mL and in 30% was >100,000 copies/mL; median baseline CD4 count was 308 cells/µL; and, per study protocol, there were no primary NRTI or PI resistance mutations. Study subjects were permitted to change treatment groups for toxicity reasons and remain in the trial.

Results at 96 weeks included the following:

  • Virologic failure (VF): rates of VF were not significantly different in the 3 treatment groups (10% in RAL, 15% in DRV/r, and 13% in ATV/r)
  • Tolerability failure (TF): rates of TF in the RAL and DRV/r groups were significantly lower than in the ATV/r group (1%, 5%, and 15%, respectively)
  • Cumulative incidence of either VF or TF: RAL was superior to both PIs, and DRV/r was superior to ATV/r (cumulative failure rates of 1%, 5%, and 16%, respectively)
    • This difference was attributable largely to tolerability issues in the ATV/r group (most common were jaundice, hyperbilirubinemia, or gastrointestinal symptoms)
  • Resistance:
    • The incidence of resistance in subjects with treatment failure was substantially higher in the RAL group (28% of those with VF and resistance test information) than in the PI groups (4% of the DRV/r group and 12% of the ATV/r group).
    • Additionally, the RAL group had more 2-class resistance than the PI groups (11/18 in the RAL group had both integrase and RT mutations, whereas the PI groups had RT mutations, plus 1 integrase mutation in each group and no protease mutations)
  • CD4 increases: >250 cells/µL in all groups
  • Metabolic effects:
    • Lipids: greater increases in LDL and TG were seen in the DRV/r and ATV/r groups than in the RAL group; there were no significant differences between the two PI groups.
    • Bone density: bone mineral density loss at the lumbar spine and total hip was less in the RAL group than in either PI group, and were not different in DRV/r versus ATV/r group.

Clinical Bottom Line

This study provides a welcome comparison of 3 standard regimens for initial HIV therapy (each is recommended by current DHHS and IAS-USA guidelines). As expected, each performed well in terms of virologic efficacy; that is, each ART regimen worked well for those able to take and tolerate it. However, the 3 regimens were differentiated by tolerability and resistance issues. ATV/r caused treatment-limiting adverse effects significantly much more frequently than did either RAL or DRV/r, and both PIs caused more lipid and bone mineral density perturbations than did RAL. Virologic failure was uncommon in each treatment group but in raltegravir recipients the consequences of VF were greater than in recipients of either PI--a greater proportion of the RAL VF group developed resistance mutations, and most had mutations to 2 ARV classes. Subjects in the DRV/r and ATV/r groups who experienced VF had NRTI mutations but no PI resistance mutations (each group also had 1 subject with an integrase mutation; this was not explained but perhaps reflects a change of treatment group during the study). Further analyses of the data should be forthcoming and may help to identify groups (eg, based on HIV RNA strata) who are more likely to succeed (or fail) with any of these regimens. For the time being, I am left with the question of whether ATV, compared to other agents, has any significant advantages for initial therapy.


  • Landovitz RL, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. In: Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 85.
  • Ofotokun I, Ribaudo H, Na L, et al. Darunavir or atazanavir vs raltegravir lipid changes are unlinked to ritonavir exposure: ACTG 5257. In: Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 746.
  • Brown T, Moser C, Currier J, et al. Bone density changes after antiretroviral initiation with protease inhibitors or raltegravir. In: Program and abstracts of the 2014 Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 779LB.

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