Switching to unboosted atazanavir reduces bilirubin and triglycerides without compromising treatment efficacy in UGT1A1*28 polymorphism carriers.

OBJECTIVES: Hyperbilirubinaemia is a frequent complication of atazanavir-containing antiretroviral therapy and its severity is related to UDP-glucuronosyl transferase (UGT) 1A1*28 polymorphism. The aim of this study was to evaluate the safety and outcome of unboosted atazanavir-containing regimens based on the genetic constitution. METHODS: Fifty-one HIV-1-infected patients on boosted atazanavir were prospectively enrolled in the study. Twenty-five patients with a UGT1A1*28 allele switched to 400 mg of unboosted atazanavir. RESULTS: At baseline, UGT1A1 heterozygous and homozygous patients had significantly higher bilirubin levels than wild-type (P = 0.012 and P < 0.001, respectively). After ritonavir removal, a reduction was observed in total bilirubin (from 4.09 to 1.82 mg/dL; P < 0.001), γ-glutamyl transpeptidase (P = 0.015), triglycerides (P = 0.03) and total cholesterol (P = 0.05). No significant changes in CD4 T cell count and no increases in viral load were observed 12 months after unboosting. Plasma drug monitoring after ritonavir removal revealed the presence of therapeutic atazanavir concentrations in all patients except one with poor therapy adherence. CONCLUSIONS: UGT1A1*28 is significantly related to hyperbilirubinaemia in HIV-1 patients receiving atazanavir. Genotyping before the initiation of antiretroviral therapy can reduce the emergence of severe hyperbilirubinaemia. Unboosted atazanavir-containing therapy is safe and efficacious in patients with an undetectable viral load with a UGT1A1*28 polymorphism, allowing the use of atazanavir in patients otherwise likely unable to receive it.

Atypical pharmacokinetics of atazanavir in an HIV-1-infected patient.

An HIV-infected patient with very low atazanavir (ATV) plasma trough concentrations despite clinical signs of poor drug tolerability was described. By therapeutic drug monitoring (TDM), the authors found that the patient had an atypical ATV pharmacokinetics characterized by rapid drug absorption followed by very fast drug clearance probably attributable to his genetic background. This case underlines the importance of traditional and pharmacogenetic-based TDM for the individualization of ATV therapy in HIV-1 patients.

Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1).

X chromosome inactivation involves initiation, propagation, and maintenance of gene inactivation. Studies of replication pattern and timing in X;autosome translocations have suggested that X inactivation may spread to autosomal DNA. To examine this phenomenon at the molecular level, we have tested the transcriptional activity of a number of chromosome 5 loci in a female subject with microcephaly, mild dysmorphic features and 46,X,der(X)t(X;5)(q22.1;q31.1) karyotype. RT-PCR analysis of 20 transcribed sequences spanning 5q31.1-qter revealed that nine of them were not expressed in somatic cell hybrid clones carrying the translocated chromosome. However, eight genes were expressed and therefore escaped inactivation. This direct expression test demonstrates that spreading of inactivation from the X chromosome to the adjoining autosomal DNA was incomplete and 'patchy'. Inactivation was associated in most instances to methylation of the CpG sequences in genes containing CpG islands, but was also present in CpG islandless genes. These results agree with those obtained for other X;autosome translocations and demonstrate that autosomes are partially resistant to Xist-mediated spreading and/or maintenance of inactivation. Repeat distribution analysis does not suggest an association between L1 and LINE repeat density on chromosome 5 and gene inactivation. The expression data may also explain why the proband manifests an attenuated clinical phenotype compared to subjects with partial chromosome 5 trisomy.