Antiretroviral Combinations Compared: Are We Closer to Declaring a Winner?

Readers of ConsultantLive may recall that 4 months ago, I posed, and attempted to answer, the following question: “Is there a best regimen for initial antiretroviral therapy?” In that posting, I mentioned that the results of an AIDS Clinical Trials Group (ACTG) trial, ACTG 5257, that compared 3 of the (then) 4 US Department of Health and Human Services (DHHS) “preferred” regimens would be presented at a major conference in the near future.

At the Conference on Retroviruses and Opportunistic Infections (CROI) 2014, the results of ACTG 5257 were presented. And while there wasn’t a clear “winner” among the 3 regimens, there did seem to be a clear “loser.” 

ACTG 5257 was a randomized, non-blinded, comparison of atazanavir/ritonavir versus darunavir/ritonavir versus raltegravir, each combined with the co-formulated, fixed-dose combination of tenofovir/emtricitabine (Truvada), and dosed according to the FDA-approved schedule (once daily for all of the drugs except raltegravir, which was dosed twice daily). The trial is noteworthy for a number of reasons: 

• It is one of the largest, if not the largest, 3-arm comparison of commonly used antiretroviral regimens.

• It enrolled a racially/ethnically diverse population that included over 25% women.

• It is the last ACTG-sponsored large-scale comparison of antiretroviral regimens for the foreseeable future.

• Participants were followed for a minimum of 96 weeks.

• It has the power to potentially answer previously unanswerable questions, such as whether one of the regimens is better for women than for men, whether one of the regimens works best for low CD4⁺ cell counts, whether one of the regimens works best at high HIV RNA copy levels, etc (analyses ongoing and not presented yet).

The study randomized in a 1:1:1 manner 1809 HIV-infected, previously treatment-naive, participants to 1 of the 3 regimens. Primary endpoints included virologic failure (VF), “tolerability failure” (TF) (ie, discontinuation of the randomized regimen because of toxicity), and combined VF/TF, each at 96 weeks.

The hypothesis was that all regimens would be equivalent for all endpoints. Results showed that there were no differences (pairwise comparisons) in VF among the 3 regimens. However, both raltegravir and darunavir/ritonavir were superior to atazanavir for TF. In addition, raltegravir was superior to both darunavir/ritonavir and atazanavir/ritonavir in the composite endpoint, and darunavir/ritonavir also was superior to atazanavir/ritonavir in the composite endpoint. 

Looking more closely at the specifics, “any” toxicity was reported by 16% of those randomized to atazanavir/ritonavir, 5% of those randomized to darunavir/ritonavir, and only 1% of those randomized to raltegravir. Clinical jaundice (ie, scleral icterus) was the predominant adverse event in the atazanavir/ritonavir arm, although discontinuations from GI side effects also occurred most frequently in that arm (4%).  On the other hand, VF associated with resistance occurred most frequently in the raltegravir arm (3%), versus 1.5% for the atazanavir/ritonavir arm and <1% for the darunavir/ritonavir arm.

Taken as a whole, the regimen that included atazanavir/ritonavir did the worst on the TF and cumulative VF/TF endpoints. The regimen that included raltegravir did the best on those same endpoints. 

The higher VF with resistance in the raltegravir arm precludes me from crowning raltegravir the clear winner. But it seems clear that the atazanavir/ritonavir arm was the clear loser on every metric except VF.

Results of the NEAT001/ANRS143 trial were also presented. That study compared the efficacy and tolerability of darunavir/ritonavir plus raltegravir versus darunavir/ritonavir plus Truvada. This trial randomized in a 1:1 fashion 805 participants to either the “standard” regimen of darunavir/ritonavir plus Truvada, or the nucleoside reverse transcriptase (NRTI)-sparing alternative regimen of darunavir/ritonavir plus raltegravir. The rationale for the study was to see if the NRTI (“nuc”) class was a necessary “backbone” of a protease inhibitor (PI)-based regimen. This trial also followed participants for a minimum of 96 weeks. 

Overall, the NRTI-sparing regimen of darunavir/ritonavir plus raltegravir was found to be non-inferior to the standard regimen of darunavir/ritonavir plus Truvada. However, VF with resistance occurred more frequently in the NRTI-sparing arm than in the standard arm (5 versus 0 with major drug-limiting mutations).

Even more interesting was the stated finding that 4 of the 5 participants failing with resistance in the raltegravir arm entered the study with a baseline HIV RNA level of more than 500,000 copies. 

These two studies, although quite different in design, demonstrate that raltegravir is an extremely well-tolerated and potent component of a combination antiretroviral regimen (cART). However, the overall barrier to the development of resistance is not as great as it is with the more “traditional” PI + 2 NRTI regimen of darunavir/ritonavir plus Truvada.

References:

References

1. Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/Tenofovir: ACTG 5257.  Abstract 85.  CROI 2014. March 5, 2014, Boston.

2. 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. March 5, 2014, Boston.