Pharmacogenetics of plasma dolutegravir exposure during 1-month rifapentine/isoniazid treatment of latent tuberculosis

Abstract

In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations with dolutegravir C trough . Among 30 participants evaluable for genetic associations, median (Q1, Q3) day 0 dolutegravir C trough was 1745 (1099, 2694) ng/ml, and day 28 was 2146 (1412, 2484) ng/ml. Day 28 C trough was higher with UGT1A1 rs887829 TT [geometric mean ratio (GMR) = 1.65; 90% confidence interval (CI): 0.97-2.78] and CT (GMR = 1.38; 90% CI: 1.02-1.86) than with CC, and was higher with AADAC rs1803155 GG (GMR = 1.79; 90% CI: 1.09-2.93) and AG (GMR = 1.48; 90% CI: 1.14-1.90) than with AA. Median day 28 C trough ranged from 1205 (1063, 1897) ng/ml with 4 total UGT1A1 and AADAC risk alleles, to 3882 and 3717 ng/ml with only one risk allele. Individuals with concomitant AADAC slow metabolizer and UGT1A1 normal metabolizer genotypes may be at greater risk for clinically significant drug-drug interactions between rifapentine/isoniazid and dolutegravir.

Keywords: CYP3A; HIV-1; UGT1A1; dolutegravir; isoniazid; pharmacogenetics; rifapentine; tuberculosis.

Fig. 1

Relationships of UGT1A1 and AADAC genotypes with dolutegravir C_trough at days 0 and 28. (a) Left side – relationship of UGT1A1 rs887829 with dolutegravir C_trough at day 0 (dolutegravir 50 mg once daily, without rifapentine and isoniazid). Right side – relationship of UGT1A1 rs887829 with dolutegravir C_trough at day 28 (dolutegravir 50 mg twice daily, with once daily rifapentine 600 mg and isoniazid 300 mg). (b) Left side – relationship of AADAC rs1803155 with dolutegravir C_trough at day 0. Right side – relationship of AADAC rs1803155 with dolutegravir C_trough at day 28. (c) Risk alleles for lower dolutegravir C_trough were defined as AADAC rs1803155 A, and UGT1A1 rs887829 C. Numbers 1–4 above the X axis indicate the total number of risk alleles. The rs887829 C/T and rs1803155 A/G genotype combinations are indicated below the X-axis. Error bars indicate the median and interquartile range. Marker positions are unadjusted for BMI. The horizontal dashed line indicates the in vitro, protein-adjusted dolutegravir IC₉₀ for wild-type HIV-1 of 64 ng/ml [13]. P-values from multivariable linear regression models are adjusted for BMI. DTG, dolutegravir; INH, isoniazid; RPT, rifapentine.