Paper # 949 
Associations between HLA to DRB1*0102, HLA to B*5801 and Hepatotoxicity in Patients Who Initiated NVP-containing Regimens: South Africa
Elizabeth Phillips*1, J Bartlett2, I Sanne3, M Lederman4, J Hinkle5, F Rousseau5, I James1, S Mallal1, and D Haas6
1Inst for Immunology and Infectious Diseases, Murdoch Univ, Perth, Australia; 2Duke Univ Med Ctr, Durham, NC, US; 3Univ of the Witwatersrand, Johannesburg, South Africa; 4Case Western Reserve Univ, Cleveland, OH, US; 5Gilead Sci Inc, Durham, NC, US; and 6Vanderbilt Univ Sch of Med, Nashville, TN, US
Background: Distinct HLA associations with
nevirapine (NVP) rash or hepatotoxicity have been found in different
populations, including HLA-DRB1*0101 in Caucasian populations and
distinct HLA-B*35 subtypes in Thai and Caucasian populations. Data are
lacking regarding HLA associations with NVP hepatotoxicity in Africa where NVP
use is most prevalent.
Methods: We performed a case-control study to
identify potential HLA associations with hepatotoxicity among HIV-infected
patients in South Africa who received NVP in the FTC-302 protocol. FTC-302 was
a prospective trial that, in 1999 and 2000, randomized HIV-infected patients to
receive FTC or 3TC. Patients with baseline HIV-1 RNA ≤100,000 copies/mL
were stratified to receive NVP, and all received d4T. Hepatotoxicity affected
66 (17%) (median baseline CD4 cell count 375/mm3, 23%) of 385
patients who initiated NVP. We matched each emergent grade 3 or greater NVP
hepatotoxicity case (ALT or AST >5 times upper limit of normal) with 2 NVP-tolerant
controls. Cases and controls were matched for race, gender, age, baseline CD4
count, and baseline HIV-1 RNA. High resolution HLA A, B, C, and DR typing was
performed using standard sequence based typing. Predictive HLA alleles
identified in univariate conditional logistic regression analyses were included
in a single multivariable model with backward elimination used to identify the
parsimonious set of significant alleles. p values were adjusted for
carriage of other alleles in the multivariable model.
Results: High-resolution HLA A, B, C, DR typing was
available on 57 hepatotoxicity cases and 111 matched controls. Multivariable
analysis identified increased risk (case/control frequencies in brackets)
associated with HLA to DRB1*0102 (RR = 4.65 [0.16/0.045] p = 0.045)
and HLA to B*5801 (RR = 3.85 [0.22/0.087], p = 0.032). Decreased
risk was associated with HLA to B*1510 (RR = 0.11 [0.074/0.21], p
= 0.007), HLA to B*5802 (RR = 0.12 [0.11/0.22], p = 0.006), and HLA
to C*0210 (RR = 0.04 [0.036/0.17], p = 0.006).
Conclusions: HLA-DRB1*0102, an allele closely
related to HLA-DRB1*0101, was associated with hepatotoxicity in South
Africans during initiation of NVP to containing regimens. As has been found
with NVP-associated hepatitis in other populations, this study of South
Africans found distinct, population-specific HLA-DR and HLA-B alleles
associated with increased risk of severe NVP hepatotoxicity.
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