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  10th International Workshop on Clinical Pharmacology of HIV Therapy
April 15-17, 2009
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Unboosted Atazanavir Plus Raltegravir Analyzed as
Two-Drug Replacement Regimen

  10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Concentrations of atazanavir (without a ritonavir boost) plus the integrase inhibitor raltegravir looked good in a study of 21 HIV-infected people switching to the two antiretrovirals [1]. The double-drug combo stirred interest at the HIV Pharmacology Workshop because both drugs have a good safety profile coupled with potent antiviral activity, and their combined use would avert nucleoside- and ritonavir-related toxicities.
Raltegravir and atazanavir may interact unfavorably because raltegravir depends on UGT-1A1 for its metabolism, and atazanavir inhibits that enzyme. In an earlier study of atazanavir given to 17 healthy volunteers at a dose of 300 mg twice daily, raltegravir at the standard dose of 400 mg twice daily lowered atazanavir minimum concentration (Cmin) 29%, while raltegravir exposure rose 40% to 55% [2]. Meanwhile, a recent comparison of 400 mg of atazanavir once daily and 200 mg twice daily in 10 people with HIV found a significantly higher trough (305 versus 138 ng/mL) and a significantly lower maximum concentration (1314 versus 2786 ng/mL) with twice-daily dosing [3]. These people were not taking raltegravir but were taking tenofovir, which can also lower atazanavir levels. Diego Ripamonti and colleagues in Bergamo and Torino recruited 21 people taking a ritonavir-boosted protease inhibitor (PI) or nonnucleoside regimen but without mutations that make HIV resistant to atazanavir. They switched to atazanavir/raltegravir (200/400 mg twice daily) because of toxicity or resistance to drugs in their current regimen. In light of the earlier study in people with HIV [3], and since raltegravir must be taken twice daily, Ripamonti divided the atazanavir dose into 200 mg twice daily instead of the usual unboosted dose of 400 mg once daily. After everyone had taken the new double-drug regimen for at least 2 weeks, he measured atazanavir and raltegravir levels before the morning dose, then 0.5, 1, 2, 3, 4, 8, and 12 hours after dosing.
All study participants were white, 81% were men, and 29% had HCV infection. Median CD4 count stood at 400, and 13 people (62%) had a viral load under 50 copies. Eight people (38%) were already taking atazanavir, all of them with a ritonavir boost. They averaged 3.3 nucleoside-related mutations and 1 nonnucleoside mutation but had no atazanavir-related mutations.
Geometric mean atazanavir Cmin in Ripamonti's study (227 ng/mL) was slightly lower than the Cmin with the twice-daily unboosted dose in the other HIV study (305 ng/mL) [3] but higher than the once-daily unboosted dose in that study (138 ng/mL). Geometric mean maximum concentration was also lower in Ripamonti's trial than with twice-daily dosing in the other study (1062 versus 1314 ng/mL). Five of 21 people in Ripamonti's study (24%) had an atazanavir Cmin below 150 ng/mL (the minimum effective concentration), equivalent to the 2 of 10 (20%) in the other HIV study.
Raltegravir 12-hour concentrations were higher in Ripamonti's patients than in the earlier study of raltegravir plus atazanavir at 300 mg twice daily in healthy volunteers [2] (geometric mean 132 versus 97.8 ng/mL). But the atazanavir Cmin was higher with the 300-mg twice-daily dose in healthy volunteers (817 ng/mL).
In Ripamonti's study, the geometric mean for atazanavir 12-hour area under the curve stood at 6257 ng/hr/ml, while other raltegravir geometric means were 9085 ng/hr/nL for 12-hour AUC and 2402 ng/mL for Cmax.
After 5 to 7 months of follow-up, everyone had a viral load below 50 copies, no one had a grade 3 or 4 lab toxicity, and no one dropped out of the study. Noting that results of this small, nonrandomized study may not apply to a wider population of antiretroviral-experienced people, Ripamonti asked whether this two-drug regimen may replace standard triple therapy for selected individuals.
1. Ripamonti D, Maggiolo F, d'Avolio A, et al. Steady-state pharmacokinetics of Atazanavir (200mg BID) when combined with Raltegravir (400mg BID) in HIV-1 infected adults. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract O-14.
2. 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, 2009, Montreal. Abstract 696.
3. Bonora S, D'Avolio A, Tettoni C, et al. A pilot study evaluating plasma and intracellular pharmacokinetics of switching from atazanavir (ATV) 400mg QD to ATV 200 mg BID in HIV+ patients. 9th International Workshop on Clinical Pharmacology of HIV Therapy, April 7-9, 2008. New Orleans. Abstract O17.