Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342)

Jose R. Castillo-Mancilla, Christina L. Aquilante, Michael F. Wempe, Laura M. Smeaton, Cynthia Firnhaber, Alberto M. LaRosa, Nagalingeswaran Kumarasamy, Adriana Andrade, Gautam Baheti, Courtney V Fletcher, Thomas B. Campbell, David W. Haas, Samantha MaWhinney, Peter L. Anderson

Research output: Contribution to journalArticle

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Abstract

Objectives: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods: Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). Results: Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median agewas 34 years.We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P=0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P=0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P=0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P=0.02, respectively. Conclusions: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

Original languageEnglish (US)
Pages (from-to)1609-1618
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume71
Issue number6
DOIs
StatePublished - Jun 13 2016

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Pharmacogenetics
Acquired Immunodeficiency Syndrome
Clinical Trials
HIV
Cytochrome P-450 CYP3A
Didanosine
Pharmacokinetics
efavirenz
Atazanavir Sulfate
Peru
Medical Genetics
Genetic Polymorphisms
South Africa
Treatment Failure
African Americans
Analysis of Variance
Parents

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings : A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342). / Castillo-Mancilla, Jose R.; Aquilante, Christina L.; Wempe, Michael F.; Smeaton, Laura M.; Firnhaber, Cynthia; LaRosa, Alberto M.; Kumarasamy, Nagalingeswaran; Andrade, Adriana; Baheti, Gautam; Fletcher, Courtney V; Campbell, Thomas B.; Haas, David W.; MaWhinney, Samantha; Anderson, Peter L.

In: Journal of Antimicrobial Chemotherapy, Vol. 71, No. 6, 13.06.2016, p. 1609-1618.

Research output: Contribution to journalArticle

Castillo-Mancilla, JR, Aquilante, CL, Wempe, MF, Smeaton, LM, Firnhaber, C, LaRosa, AM, Kumarasamy, N, Andrade, A, Baheti, G, Fletcher, CV, Campbell, TB, Haas, DW, MaWhinney, S & Anderson, PL 2016, 'Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342)', Journal of Antimicrobial Chemotherapy, vol. 71, no. 6, pp. 1609-1618. https://doi.org/10.1093/jac/dkw005
Castillo-Mancilla, Jose R. ; Aquilante, Christina L. ; Wempe, Michael F. ; Smeaton, Laura M. ; Firnhaber, Cynthia ; LaRosa, Alberto M. ; Kumarasamy, Nagalingeswaran ; Andrade, Adriana ; Baheti, Gautam ; Fletcher, Courtney V ; Campbell, Thomas B. ; Haas, David W. ; MaWhinney, Samantha ; Anderson, Peter L. / Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings : A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342). In: Journal of Antimicrobial Chemotherapy. 2016 ; Vol. 71, No. 6. pp. 1609-1618.
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abstract = "Objectives: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods: Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95{\%} CI). Results: Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median agewas 34 years.We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P=0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P=0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P=0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P=0.02, respectively. Conclusions: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.",
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T1 - Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings

T2 - A sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342)

AU - Castillo-Mancilla, Jose R.

AU - Aquilante, Christina L.

AU - Wempe, Michael F.

AU - Smeaton, Laura M.

AU - Firnhaber, Cynthia

AU - LaRosa, Alberto M.

AU - Kumarasamy, Nagalingeswaran

AU - Andrade, Adriana

AU - Baheti, Gautam

AU - Fletcher, Courtney V

AU - Campbell, Thomas B.

AU - Haas, David W.

AU - MaWhinney, Samantha

AU - Anderson, Peter L.

PY - 2016/6/13

Y1 - 2016/6/13

N2 - Objectives: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods: Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). Results: Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median agewas 34 years.We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P=0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P=0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P=0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P=0.02, respectively. Conclusions: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

AB - Objectives: The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods: Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). Results: Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median agewas 34 years.We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P=0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P=0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P=0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P=0.02, respectively. Conclusions: Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

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