Among the 321 evaluable patients, 120 (37.5%) had rs887829 C/C, 142 (44%) had C/T, and 59 (18.5%) had T/T genotype. Among 59 patients homozygous for rs887829 T/T, 43 (73%) were Black, 13 (22%) were White, and three (5%) were Hispanic. Homozygosity for rs887829 T/T was present in 28.1% of Black, 21.4% of Hispanic, and 8.6% of White patients (Table 3).
Among the 321 evaluable patients, in analyses adjusted for the first two MDS coordinates, the hazard ratio (HR) for bilirubin-related atazanavir discontinuation with T/T genotype was 7.4 [95% confidence interval (CI): 1.7–31.5; P=0.007], and with C/T genotype was 1.5 (95% CI: 0.5–8.4; P=0.30). Time to bilirubin-related atazanavir discontinuation stratified by genotype is shown in Fig. 1a. Among 152 White patients, unadjusted HRs for discontinuation with T/T and C/T genotypes were 14.4 (95% CI: 2.6–78.7; P=0.002) and 1.3 (95% CI: 0.2–9.4; P=0.78), respectively (Fig. 1b). Among 153 Black patients, unadjusted HRs with T/T and C/T genotypes were 0.8 (95% CI: 0.1–12.7; P=0.87) and 1.4 (95% CI: 0.1–13.6; P=0.77), respectively (Fig. 1). Among 14 Hispanic patients, two had bilirubin-related atazanavir discontinuation, including one of three with T/T, and one of seven with C/T genotypes (Fig. 1d).
The above analyses did not consider pretreatment baseline bilirubin as a covariate. At baseline, six patients had bilirubin concentrations above the normal range, including five with bilirubin between 1.1 and 1.3 mg/dl, and one with a bilirubin of 2.3 mg/dl. Among the 321 evaluable patients, in analyses adjusted for the first two MDS coordinates, the HR of baseline bilirubin concentration for bilirubin-related atazanavir discontinuation was 7.3 (95% CI=2.6–20.7; P<0.001). In a multivariable model that included rs887829 genotype, baseline bilirubin concentration, and 2 MDS coordinates, the HR for discontinuation was significant for T/T genotype (HR=5.2; 95% CI: 1.1–24.5; P=0.038) but not for baseline bilirubin (HR=2.0; 95% CI: 0.8–4.9; P=0.14). With this same multivariable model but just including White patients, the HR for discontinuation was significant for T/T genotype (HR=9.4; 95% CI: 1.3–66.9; P=0.026) but not for baseline bilirubin (HR=5.2; 95% CI: 0.7–40.4; P=0.11). With this model but just among Black patients, the HR for discontinuation was not significant for T/T genotype (HR=0.30; 95% CI: 0.01–6.7; P=0.45) but was significant for baseline bilirubin, with an extremely wide confidence interval (HR=140.6; 95% CI: 3.6–5481; P=0.008).
This study replicates a difference by race that was first reported in analyses on the basis of data from ACTG clinical trial A5257 19. In that study there was a much stronger association between UGT1A1 slow metabolizer genotype and increased bilirubin-related atazanavir discontinuation among 183 White patients (HR=24, P=1.3×10−4) than among 211 Black patients (HR=10, P=0.03). A similar association in a largely Caucasian cohort was seen in an observational study involving 121 Swiss HIV Cohort Study participants (80% Whites) who had received atazanavir/r, in which carriage of UGT1A1 low expresser alleles (*28/*28 or *28/*37) was associated with increased risk of atazanavir/r discontinuation, with cumulative rates of 63% among 18 participants carrying two alleles, 24% among 48 participants carrying one allele, and 15% among 55 participants carrying no allele 19.
It is possible that providers queried Black patients less than White patients regarding reasons for discontinuing atazanavir. However, this is unlikely as all patients received care at a single HIV primary care clinic where, since 1997 every antiretroviral treatment change is presented and thoroughly discussed at a multidisciplinary Antiretroviral Therapy Conference. There is strong evidence that bilirubin concentrations with atazanavir/r are similar among Black patients and White patients with UGT1A1 slow metabolizer genotypes 16, so this is unlikely to explain the difference by race/ethnicity.
This work was supported in part by the National Institute of Allergy and Infectious Diseases grants R01 AI077505, P30 AI110527, and UL1 TR002243 (DWH), and by Fogarty International Center and National Institute of Mental Health award D43 TW009608 (J.N.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
There are no conflicts of interest.
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