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Resistance and Bilirubin Derail Twice-Daily Raltegravir/Atazanavir
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XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
IAC: The SPARTAN Study: A Pilot Study to Assess the Safety and Efficacy of an Investigational NRTI- and RTV-Sparing Regimen of Atazanavir (ATV) Experimental Dose of 300mg BID plus Raltegravir (RAL) 400mg BID (ATV+RAL) in Treatment-Naïve HIV-Infected Subjects - (07/22/10)
Previously untreated adults had similar virologic responses to 24 weeks of (1) raltegravir plus unboosted atazanavir twice daily and (2) once-daily standard-dose atazanavir/ritonavir plus tenofovir/emtricitabine (Truvada) [1]. Atazanavir levels were higher in the 300-mg twice-daily arm, with its experimental atazanavir dose, than in people treated with atazanavir/ritonavir plus Truvada in earlier studies. Because of a high elevated bilirubin rate in the experimental arm and emergence of raltegravir-resistant virus upon failure, the trial stopped at 24 weeks, and makers of atazanavir and raltegravir will not pursue this particular strategy.
The goal of the twice-daily raltegravir/atazanavir regimen was to control HIV as well as standard triple therapies in antiretroviral-naive people while sparing them the toxicities of reverse transcriptase inhibitors and low-dose ritonavir. But before the trial began, the novel regimen already had the disadvantage of twice-daily dosing versus several well-tested, effective once-daily combinations.
This trial by clinical investigators in the US, Argentina, and France randomized 63 people to raltegravir/atazanavir (400/300 mg twice daily) and 31 to atazanavir/ritonavir plus Truvada. Everyone had a viral load above 5000 copies, and half had a load above 100,000 copies. This pilot trial, called SPARTAN, was not powered to detect significant response differences between study arms.
Median age at enrollment was close to 40 years in both arms, and about 90% of study participants were men. The triple-therapy arm had a higher proportion of African Americans (20.0% versus 12.7%). Pretreatment viral load averaged 4.9 log copies (80,000 copies) in both arms, and similar proportions started the study with a load above 100,000 copies (54% with atazanavir/raltegravir and 43% with triple therapy). Pretreatment CD4 count averaged 256 in the experimental arm and 261 in the control arm.
Six of 63 people (9.5%) stopped atazanavir/raltegravir, 2 of them with jaundice. All 6 of these people had a viral load below 50 copies when they dropped out. Three of 30 people (10%) who began treatment in the triple-therapy arm stopped
In a 24-week noncompleter-equals-failure analysis, 47 of 63 people (74.6%) on raltegravir/atazanavir versus 19 of 30 (63.3%) on the triple regimen had a viral load below 50 copies. With noncompleters excluded from the analysis, 47 of 58 (81%) on raltegravir/atazanavir and 19 of 27 (70.4%) on triple therapy had a 24-week viral load below 50 copies. In both analyses, the response rates with the standard regimen looked low at 24 weeks, but at 48 weeks 76% taking triple therapy and 82.2% taking raltegravir/atazanavir had a viral load under 50 copies.
Eleven people randomized to raltegravir/atazanavir (17.5%) and 8 (26.7%) randomized to triple therapy had a viral load above 50 copies at week 24. Defining virologic failure as a viral load above 400 copies at week 24, the investigators counted 6 failures (9.5%) in the raltegravir/atazanavir group and 1 (3.3%) in the standard-therapy group. (from Jules: 8/11viral failures on ATV+RAL had a baseline HIV VL>250,000; 4/8 viral failures on ATV/RTV+TDF/FTC had a baseline VL>250,000). Raltegravir-related mutations emerged in 4 of these 6 people (66.7%) taking the integrase inhibitor, while no protease mutations emerged in this group. Only 1 person in the triple-therapy group had a week 24 viral load above 400 copies, and no protease or reverse transcriptase mutations could be detected in this person.
Grade 2 to 4 treatment-related hyperbilirubinemia developed in 19 people (30.2%) taking raltegravir/atazanavir and in 10 (33.3%) taking the standard regimen. Grade 4 hyperbilirubinemia occurred in 13 people (20.6%) on raltegravir/atazanavir and in no one in the other group. Four people (6.3%) stopped raltegravir/atazanavir and none stopped the other regimen because of treatment-related side effects.
In 13 people with drug level monitoring, raltegravir concentrations were similar to levels in historical controls. But atazanavir concentrations were higher than levels seen earlier among people taking atazanavir/ritonavir plus Truvada.
"Lipids were favorable on ATV/RAL including big increase in HDL and TG decreased"
Reference
1. Kozal M, Lupo S, DeJesus E, et al. The SPARTAN study: a pilot study to assess the safety and efficacy of an investigational NRTI- and RTV-sparing regimen of atazanavir (ATV) experimental dose of 300mg BID plus raltegravir (RAL) 400mg BID (ATV+RAL) in treatment-naive HIV-infected subjects. XVIII International AIDS Conference. July 18-23, 2010. Vienna. Abstract THLBB204.
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