Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by >3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C tau , or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C tau , area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and raltegravirglucuronide/raltegravir AUC 0-12 were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reductionof-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C tau with a once-daily raltegravir dose of 400 mg similar to the C tau with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.In 2007, 4 million HIV-infected patients were taking antiretroviral medications in countries with low to middle income levels, according to the World Health Organization (WHO) (24). According to the 2009 update (23) of the WHO treatment guidelines (22), recommended first-line therapies should include two nucleoside reverse transcriptase inhibitors (NRTI) and either efavirenz or nevirapine. However, efavirenz is classified by the United States Food and Drug Administration (FDA) as a "D" drug during pregnancy, due to teratogenic potential demonstrated in monkeys and in retrospective human data, which means it is not recommended for women of child-bearing age who cannot practice reliable contraception. Nevirapine has a "black box" warning advising of increased risk of severe or fatal hepatotoxicity if used in women with CD4 ϩ cell counts of Ͼ250 cells/ml. Therefore, there is room for additional first line and even salvage agents that are potentially affordable, safe, well-tolerated, and independent of current, widely used first-or second-line therapies. Raltegravir could be one of these new drugs, but its high cost, which is prohibitive for most of the world's HIV-infected patients (16), warrants investigation into strategies, such as boosting, to redu...