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Maintenance With Raltegravir/Atazanavir
Usually Effective for 48 Weeks (low troughs, a few viral rebounds)
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50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
Twice-daily raltegravir plus once-daily atazanavir (without a ritonavir boost) maintained an undetectable viral load in 27 of 30 patients for 48 weeks [1].This small, single-center study found low atazanavir troughs in many patients, but low troughs did not predict virologic failure.
Two-drug regimens including the integrase inhibitor raltegravir or the CCR5 antagonist maraviroc, usually with a protease inhibitor (PI), have come under close scrutiny in small studies because of their potential potency, convenience, and tolerable toxicity. A trial that randomized previously untreated people to atazanavir/ritonavir plus tenofovir/emtricitabine or to twice-daily raltegravir plus unboosted atazanavir at 300 mg twice daily ended early because of elevated bilirubin and integrase resistance mutations in the raltegravir/atazanavir arm [2].
The single-center study at a Los Angeles clinic involved 30 people with an undetectable load who switched to raltegravir/atazanavir (400 mg twice daily/400 mg once daily) because of intolerance of their current regimen. No one had an earlier PI mutation or a record of atazanavir intolerance. No one had taken raltegravir.
All study participants except 1 were gay men, and their median age was 47. Twenty-four were white. Twenty-seven of the 30 were taking a PI regimen, and 19 had taken atazanavir. Everyone was taking a stable antiretroviral combination for at least 2 months, with a viral load below 400 copies for more than 4 months, and everyone had a load below 50 copies at study entry. The investigators monitored adherence by patient self-report and by raltegravir pill count at each visit. They defined virologic failure at two viral loads above 400 copies 2 weeks apart.
In a missing-data-equal-failure analysis, 27 of 30 people (90%) had a week-48 viral load below 400 copies, the primary endpoint. Twenty-five of 30 people (83%) had a load below 50 copies at week 48.
Three people stopped the experimental regimen before week 48 and 1 stopped at week 48: 1 person had a viral rebound at week 8 while taking the anticonvulsant phenytoin, which lowers concentrations of some PIs; 1 person had a viral load slowly rising between 50 and 400 copies and withdrew at week 48; 1 person withdrew with rising creatinine; and 1 person died of lung cancer at week 36. Three people stopped treatment between weeks 48 and 96, 1 because of virologic failure, 1 because of persistent viremic blips (all below 400 copies), and 1 person withdrew consent.
At the time of this report, 24 of the original 30 men (80%) had remained on raltegravir/atazanavir for at week 72 weeks, and 22 of those 24 had a viral load below 48 copies. Twelve people had reached 96 weeks of treatment, 11 with a viral load below 48 copies.
Steady-state atazanavir troughs measured in 25 people proved highly variable, with a trough ranging from 0 to 539 ng/mL (median 72.3 ng/mL). Twenty people had troughs below 150 ng/mL (from Jules: which is the trough level BMS recommends), and 6 had troughs below 50 ng/mL. Atazanavir could not be detected in 3 people at the trough measurement. Of the 2 people with virologic rebounds during the trial, 1 had an undetectable atazanavir trough and 1 had a trough of 270 ng/mL. An earlier study found below-normal atazanavir levels in healthy volunteers taking 400 mg of raltegravir twice daily with 300 mg of atazanavir twice daily [3].
Only one study participant had self-reported adherence below 90%, and this person did not have a virologic rebound.
Rates of grade 2 or 3 bilirubin elevations were 27% at study entry, 36% at week 24, and 45% at week 48. But no one withdrew because of high bilirubin or scleral icterus. Total-to-high-density-lipoprotein cholesterol varied little during the study. Median total and low-density lipoprotein cholesterol values were unchanged at week 24 and mildly increased at week 48.
References
1. Ruane PJ, Wolfe PR. Dual maintenance therapy with raltegravir 400 mg bid with atazanavir 400 mg qd in patients with no prior PI resistance and intolerance to other ATV regimens: follow up report. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-205.
2. 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. http://www.natap.org/2010/IAS/IAS_86.htm
3. Zhu L, Mahnke L, Butterton J, et al. Pharmacokinetics and safety of twice-daily atazanavir (300 mg) and raltegravir (400 mg) in healthy subjects. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2010. Montreal. Abstract 696. http://www.retroconference.org/2009/Abstracts/33949.htm
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