CYP2B6-516 Genetic Variants Affect the Pharmacokinetics of Nevirapine and Clinical Responses in HIV-1-infected Children Receiving HAART
Akihiko Saitoh*1, E Sarles1, E Capparelli1, F Aweeka2, A Kovacs3, S Burchett4, A Wiznia5, S Nachman6, T Fenton7, and S Spector1
1Univ of California, San Diego, US; 2Univ of California, San Francisco, US; 3Univ of Southern California, Los Angeles, US; 4Harvard Med Sch, Boston, MA, US; 5Jacobi Med Ctr, Bronx, NY, US; 6State Univ of New York at Stony Brook Hlth Sci Ctr, US; and 7Harvard Sch of Publ Hlth, Boston, MA, US
Background: Genetic polymorphisms in drug metabolizing enzymes and transporters
affect ART drug disposition. These factors along with maturational changes
likely affect ART pharmacokinetics in children; however, their potential influence
on pharmacokinetics and clinical outcomes are not well characterized. It has
been shown that the gene polymorphism cytochrome P450
2B6 (CYP2B6)-G516T is associated with decreased activity of CYP2B6 in liver and
increased plasma efavirenz (EFV) levels, but no data are available regarding
the impact of the CYP2B6-G516T on the
pharmacokinetics of nevirapine (NVP) in children.
Methods: In 126 children from the Pediatric AIDS Clinical Trials
Group (PACTG) 366 and 377 cohorts, who received NVP and protease inhibitors
(PI, nelfinavir [NFV], or ritonavir [RTV]) as a part
of HAART regimens, real-time polymerase chain reaction (RT-PCR) was used to
genotype polymorphisms of CYP2B6.
Pharmacokinetic data at week 4 was used to calculate area under the curve (AUC)
by the trapezoidal rule and determine clearance. Immunologic and virologic data were also collected during HAART.
Results: Of the 126 children, 50 (40%) had the CYP2B6-516-G/G (wild type), 63 (50%) had the G/T (heterozygous),
and 13 (10%) had the T/T genotype (homozygous). The age, gender,
race/ethnicity, concomitant PI regimens, baseline HIV-1 RNA, and CD4 T cell
percentage were not different among the 3 groups (p = 0.16 to 0.89). NVP AUC in children with the T/T genotype (95.0
µg*hr/mL) was significantly higher than those with the
G/G (57.8 µg*h/mL, p = 0.004) and G/T genotype (58.3 µg*h/mL,
p = 0.003). NVP clearance in children
with the CYP2B6-516-T/T genotype (1.6
L/h/m2) was significantly decreased compared to those with the G/G
(2.3 L/h/m2, p = 0.001)
and G/T genotype (2.1 L/h/m2, p
= 0.003). Children with the T/T genotype had a significant increase in CD4 T
cell percentages (+7.0%) compared to those with the G/G (+3.4%, p = 0.008) and G/T genotype (+5.5%, p = 0.04) at week 12. This trend
continued at week 24 (p = 0.01). Furthermore,
in a subset of subjects whose HIV-1 RNA data were available (n = 58), children with the CYP2B6-516-T/T genotype had a more rapid
decline of log HIV-1 RNA (–39%) compared to those with the G/G (–18%, p = 0.002) and G/T genotype (–14%, p = 0.006) from baseline to week 12.
Conclusions: The CYP2B6-G516T genotype alters NVP pharmacokinetics,
as well as immunologic and virologic responses to NVP-containing HAART regimens
in children. These data suggest that the CYP2B6-G516T
is an important genetic variant that alters the pharmacokinetics of
non-nucleoside reverse transcription inhibitors (NNRTI) and may impact the
response to HAART regimens containing NVP or EFV.