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Raltegravir and Unboosted Atazanavir as Simple Maintenance Regimen
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5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town
Mark Mascolini
Twice-daily doses of atazanavir unboosted by ritonavir and the integrase inhibitor raltegravir proved safe and usually effective as a maintenance regimen in a small noncomparative study [1]. No one stopped either antiretroviral because of side effects during a half-year of follow-up.
Diego Ripamonti and colleagues in Bergamo, Italy listed several potential advantages of this nucleoside-sparing regimen: Both drugs have proved effective as key ingredients of multidrug combinations; atazanavir and raltegravir inhibit HIV at different steps in the viral replication cycle; both drugs are "lipid friendly" and generally well tolerated; neither antiretroviral requires refrigeration; an atazanavir/raltegravir regimen avoids potential toxicities of nucleoside/nucleotide reverse transcriptase inhibitors; and atazanavir can be given without ritonavir, which can be toxic even at low doses.
Earlier research showed that people switching from 400 mg of unboosted atazanavir once daily to 200 mg twice daily attained higher atazanavir trough concentrations, lower maximum concentrations, and equivalent area-under-the-curve values [2]. When atazanavir and raltegravir were combined in healthy volunteers at doses of 300/400 mg twice daily, atazanavir minimum concentration was 29% lower with than without raltegravir, while the raltegravir minimum concentration was 48% higher with atazanavir [3].
Ripamonti and coworkers tested atazanavir/raltegravir at a twice-daily dose of 200/400 mg in 27 people taking a protease inhibitor (PI) or nonnucleoside. No one had major protease mutations, no one had tried raltegravir before, and no one was taking a proton pump inhibitor, which can lower atazanavir levels. Eight study participants (30%) were women and 5 (18.5%) had hepatitis C virus infection. Their age averaged 46 years (+/- 9 standard deviation [SD]).
Twenty-two people were taking a PI, including 8 taking boosted atazanavir and 2 taking unboosted atazanavir. Five people were taking a nonnucleoside before switching to atazanavir plus raltegravir. Twenty-two people started the new regimen because of poor tolerability or toxicity, and 5 because of resistance mutations. When they switched to atazanavir/raltegravir, 16 people (59%) had a viral load under 50 copies (range of detectable loads 96 to 59,000). At that point the median CD4 count measured 417 (interquartile range [IQR] 318 to 726). Median nadir (lowest-ever) CD4 count stood at 79 (IQR 29 to 223). The number of nucleoside-related mutations at the switch averaged 3.2 (range 0 to 27) and nonnucleoside mutations 1.3 (range 0 to 3).
After 24 weeks, all but 2 people (7%) had a viral load under 50 copies. One person with a detectable load started atazanavir/raltegravir with 46,351 copies and had 1421 copies at month 3. Genotyping at this point disclosed the raltegravir-related N155H mutation. Two months after restarting boosted atazanavir with tenofovir/emtricitabine, this patient had a viral load of 87 copies. The second person with a load above 50 copies switched to atazanavir/raltegravir with a load of 279 copies and had 349 copies at week 24. Virus sampled from this patient bore 8 reverse transcriptase mutations and 2 protease mutations but no mutations in integrase. This patient continued the two-drug regimen and had a viral load of 107 copies 4 months later.
Lipid profiles did not change after the switch, and total bilirubin averaged 2.0 (+/- 1.8 SD) mg/dL. No one stopped atazanavir or raltegravir or reduced a dosage because of side effects or lab abnormalities, including treatment-limiting jaundice. Ripamonti and colleagues recorded no clinically significant changes in laboratory values.
In a pharmacokinetic analysis involving 21 people [4], geometric mean atazanavir minimum concentration (227 ng/mL) was slightly lower than the minimum concentration with the twice-daily unboosted dose in the other referenced study (305 ng/mL) [2] 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 minimum concentration below 150 ng/mL (the minimum effective concentration), equivalent to the 2 of 10 (20%) in the other study.
The investigators suggested that twice-daily raltegravir with twice-daily unboosted atazanavir may be a viable regimen, at least for people switching from another combination with well-controlled viral replication. But Ripamonti cautioned that longer follow-up in a comparative trial is needed to prove the safety and efficacy of this strategy.
References
1. Ripamonti D, Maggiolo F, Bombana E, et al. Efficacy, safety and tolerability of dual therapy with raltegravir and atazanavir in antiretroviral experienced patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract MOPEB067.
2. 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.
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, 2009. Montreal. Abstract 696.
4. 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.
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