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SPARTAN: Two-Drug, NRTI-Sparing Regimens Continue to Disappoint

Summary and Comment |
June 11, 2012

SPARTAN: Two-Drug, NRTI-Sparing Regimens Continue to Disappoint

  1. Paul E. Sax, MD

Resistance rates were higher with raltegravir + unboosted atazanavir than with tenofovir/FTC + boosted atazanavir.

  1. Paul E. Sax, MD

Current guidelines recommend that initial HIV treatment contain at least three antiretrovirals, including a pair of nucleoside reverse transcriptase inhibitors (NRTIs), but interest in two-drug, NRTI-sparing regimens persists. In the SPARTAN study, researchers tested a regimen that excludes both NRTIs and ritonavir.

Ninety-three treatment-naive, HIV-infected patients were randomized 2:1 to receive either a two-drug regimen of raltegravir (400 mg twice daily) + unboosted atazanavir (300 mg twice daily) or a standard regimen of tenofovir/FTC + ritonavir-boosted atazanavir. The study was sponsored by the maker of atazanavir.

The higher atazanavir dose in the two-drug arm attained atazanavir exposures comparable to those achieved with ritonavir boosting. At week 24, virologic suppression rates numerically favored the two-drug regimen (75% vs. 63%). However, there were six virologic failures in the two-drug group — versus only one in the standard-therapy arm — and four of these failures showed evidence of raltegravir resistance. Notably, all four patients with resistance had baseline viral loads >100,000 copies/mL. Rates of grade 3–4 and grade 4 hyperbilirubinemia were also higher in the two-drug arm than in the standard-therapy arm. Based on these results, the study sponsors elected to terminate the trial.

Comment

As a small pilot study, this trial was not powered for a statistical comparison between the two treatment arms. However, the findings are consistent with those of previous studies, which have shown suboptimal outcomes with initial two-drug, NRTI-sparing regimens, even when they include our best drugs. Why these two-drug regimens do not perform as well as standard regimens, especially in patients with high viral loads, is unclear. Do the NRTIs provide some key antiviral component mechanistically? Do we just not have the right two active drugs? Or is there something magical about using three drugs instead of two, regardless of mechanism of action? Results of the fully powered NEAT study — which compares raltegravir to tenofovir/FTC, each with boosted darunavir — will be of great interest, as will a similar study that uses maraviroc instead of raltegravir.

Citation(s):

Reader Comments (1)

Rob Camp

Paul, rather than say that two drugs "continue to disappoint" (the title), maybe we could say that starting ART with two drugs, especially at high viral loads, may not work as well. At the end of the day, what we are looking for is a regimen that is efficacious and durable, but that does the most limited damage adverse events-wise. Maybe an interesting option after 6 months (random as that is!) of being undetectable would be to see if unboosted ATZ plus RAL worked as well as boosted ATZ + TRV? And maybe body weight can be used to decide how much ATZ to give, rather than 300 BID to everyone, to see if bibirubin can be contained. Thanks very much for all your hard work.

Competing interests: (I'm really not an IM specialist, but I had to choose something. I am a patient educator.)

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