Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.

OBJECTIVES: To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR). METHODS: DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants ('cases') with clinically diagnosed abacavir HSR. RESULTS: The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR 'cases', an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six 'cases'. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants. CONCLUSION: The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.

Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial.

BACKGROUND: No data on once-daily dosing of nucleoside analogues in African children currently exist. We compared the pharmacokinetics (PK) of once- versus twice-daily lamivudine and abacavir treatment using the World Health Organization recommended weight band dosing of scored adult tablets. METHODS: HIV type-1 (HIV-1)-infected Ugandan children aged 3-12 years receiving antiretroviral therapy that included lamivudine and abacavir twice daily (total 150+300 mg, 225+450 mg and 225/300+600 mg daily for 12-<20, 20-<25 and ≥25 kg, respectively) were enrolled in a crossover study. Plasma PK sampling (at 0, 1, 2, 4, 6, 8 and 12 h after observed morning intake) was performed for the twice-daily regimen at steady-state. Children were then switched to once-daily treatment with PK sampling repeated 4 weeks later (with an additional 24 h sample). Acceptability questionnaires were completed at both time points. Daily area under the curve (AUC(0-24)) and maximum concentrations (C(max)) were compared by geometric mean ratios (GMRs). RESULTS: A total of 41 HIV-1-infected children (median age of 7 years) and n=23, n=14 and n=4 in 12-<20, 20-<25 and ≥25 kg weight bands, respectively, were enrolled. Mean AUC(0-24) was 13.0 and 12.0 mg•h/l for once- and twice-daily lamivudine (GMR 1.09, 90% confidence intervals [CI] 0.98-1.20) and 15.3 and 15.6 mg•h/l for once- and twice-daily abacavir (GMR 0.98, 90% CI 0.89-1.08), respectively, with no difference in 3-6 versus 7-12 year olds. C(max) was 76% (lamivudine) and 64% (abacavir) higher on once-daily regimens. For both children and caregivers, once-daily dosing of lamivudine plus abacavir was highly acceptable and strongly preferred over twice-daily. CONCLUSIONS: In children aged 3-12 years, AUC(0-24) of lamivudine and abacavir were bioequivalent on once- and twice-daily regimens. Once-daily dosing of abacavir and lamivudine could provide an alternative dosing strategy for HIV-1-infected children, with high acceptability and strong preference suggesting the potential for improved adherence.