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Pharmacogenomics and HIV pharmacotherapy ‘The completion of the Human Genome Project has increased the potential of pharmacogenomics to individualize HIV pharmacotherapy based on genetic characterization prior to and during antiretroviral treatment.’ Expert Rev. Clin. Pharmacol. 1(1), 5–8 (2008)
Qing Ma† and Gene D Morse † Author for correspondence University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 243 Fax: +1 716 645 2886 [email protected]
10.1586/17512433.1.1.5
The introduction of pharmacogenomics into toward personalized HIV pharmacotherapy, a HIV pharmacotherapy has provided new paradigm shift from ‘one dosing regimen fits prospects for predicting treatment efficacy all’ to ‘the right regimen for the right patient and the reduction of potential adverse effects. at the right dose and time’ [2]. HIV/AIDS is now considered a serious but There have been significant decreases in treatable chronic infectious disease; however, morbidity and mortality since the implementalong-term viral suppression with current tion of highly active antiretroviral combinaantiretroviral treatment is impacted by tions; however, the perceived need for individadverse drug reactions and drug toxicity, ualization of HIV pharmacotherapy is sometimes leading to reduced medication primarily attributed to the considerable interadherence and the development of viral resist- patient variability in drug exposure to each ance in a significant proportion of patients. antiretroviral component of a combination regThe important role of pharmacogenomics in imen, the subsequent responses and side-effect overcoming these therapeutic challenges is profiles [3]. Traditional approaches utilized for increasingly recognized through the presenta- dose adjustment based on body weight and tion of new clinical and consideration of renal translational research at and/or liver function do not ‘The introduction of HIV/AIDS conferences pharmacogenomics into normalize these interpatient and in recent publications. HIV pharmacotherapy differences. The intrinsic In addition to pharmacopotency of individual has provided new genomic aspects of antiretrovirals and their use antiretroviral metabolism prospects for predicting in potent combination regiand cell membrane trans- treatment efficacy and mens contribute to the port, genetic determinants long-term morbidity that is the reduction of may influence antiviral potential adverse effects.’ associated with HIV pharresponses to HIV pharmamacotherapy in certain cotherapy and long-term outcomes. Screen- patients that respond with more toxicity than ing for the presence of alleles associated with the average patient population. The ability to drug disposition or antiviral responses could identify the genetic factors involved in the drug be utilized to individualize antiretroviral dos- disposition, inadequate response or occurrence ages and to guide the selection of appropriate of adverse effects is the goal of pharmacogealternative therapies [1], providing optimized nomic testing and, with further research, we regimen design and prognostic profiles for should ultimately reduce the unpredictable patient subpopulations. A pharmacogenomics- nature of chronic HIV pharmacotherapy, based treatment approach will represent a step making personalized HIV medicine a reality.
© 2008 Future Drugs Ltd
ISSN 1751-2433
5
Ma & Morse
Pharmacogenomics offers a powerful new tool to investigate variable responses to antiretroviral therapy. The completion of the Human Genome Project has increased the potential of pharmacogenomics to individualize HIV pharmacotherapy based on genetic characterization prior to and during antiretroviral treatment. It has been proposed that therapeutic decisions based on the integration of therapeutic drug monitoring with viral genotyping and phenotyping may be further enhanced by the incorporation of patient genomics [4]. To date, some antiretrovirals have demonstrated a genotype–phenotype correlation (TABLE 1). These correlations have been established for cytochrome P450 (CYP)2B6 and efavirenz disposition [5,6], HLA-B and abacavir hypersensitivity [7,8], and UGT1A1 and atazanavir hyperbilirubinemia [9,10]. However, more research is needed to explore the relationship of polymorphisms, particularly utilizing gene–gene interaction analysis, to investigate pharmacokinetic and pharmacodynamic outcomes. Until these investigations are conducted, the clinical implications of present pharmacogenomic advances should be interpreted with caution. It has been increasingly recognized that genetic differences among ethnic groups may be an important determinant in disease risk, progression, prognosis and response to treatment. In recent years, the research on pharmacogenomic differences among ethnic groups has broadened to include a larger range of targets, such as multiple enzymes that regulate drug metabolism,
cell membrane drug transporters and receptors [11]. Furthermore, increasing evidence suggests that drug metabolism alone does not account for the observed inter-racial variability in drug disposition or response but other processes, such as membrane transport, are also important determinants. Among the drug transporters shown to play a key role in drug disposition, P-glycoprotein encoded by the ABCB1 gene is one of the most extensively studied. The wild-type alleles (CC) of the ABCB1 gene at the 3435C>T locus are more prevalent in the African–American population than in Caucasians and Hispanics [12,13]. Such racial differences in ABCB1 polymorphisms may contribute to previously recognized racial differences in the clinical response to antiretrovirals [14]. In the near future, pharmacogenomics may have the most immediate application in HIV pharmacotherapy with respect to race/ethnicity and sex-related differences in pharmacokinetics and pharmacodynamics. A growing body of literature has highlighted the different distribution of genetic variants among ethnic groups. A recent example is the observed high correlation between HLA-B*5701 genotype and abacavir hypersensitivity, and its rapid evolution toward an application of translational pharmacogenomics. However, the study by Mallal et al. that demonstrated this correlation was conducted primarily in Caucasian males from Australia [7]; therefore, the results from this study are difficult to extrapolate to other ethnicities. Despite recent
Table 1. Genetic polymorphisms that influence the metabolism, transport and toxicity of antiretrovirals*. Gene
SNP
Effect
Confirmation
CYP3A4
Multiple
No effect on nelfinavir or efavirenz
No
CYP3A5
6986A>G
No effect on nelfinavir or efavirenz, higher saquinavir exposure
No
CYP2B6
516G>T
Higher efavirenz exposure and increased toxicity
Yes
CYP2C19
681G>A
Higher nelfinavir exposure and decreased virological failure
No
CYP2D6
Multiple
Trend to higher nelfinavir and efavirenz concentrations
No
3435C>T
Controversial effect on antiretroviral concentrations
No
2677G>T
No effect on efavirenz, protease inhibitors or viral decay
Yes
ABCC1
Multiple
No effect on nelfinavir or efavirenz
No
ABCC2
Multiple
No effect on nelfinavir or efavirenz, increased renal toxicity from tenofovir
No
APOC3/APOE
Multiple
Development of hyperlipidemia
Yes
TNF
238G>A
Development of lipoatrophy
No
HLA-B
HLA-B*57.1
Abacavir hypersensitivity
Yes
HLA-DR
HLA-DRB1*0101
Nevirapine hypersensitivity
No
UGT1A1
UGT1A1*28 UGT1A1*6
Gilbert’s syndrome, hyperbilirubinemia in presence of atazanavir and indinavir
Yes
Metabolism
Transport ABCB1
Toxicity
*
A comprehensive HIV pharmacogenomics reference table is accessible and constantly updated at the HIV pharmacogenomics website [102].
6
Expert Rev. Clin. Pharmacol. 1(1), (2008)
Pharmacogenomics and HIV pharmacotherapy
study findings of a clear relationship between HLA type and abacavir hypersensitivity in white females and Hispanics [8], it remains unclear if screening Asians and African–Americans should be widely accepted, as the prevalence of HLA-B*5701 is less than 1% in these populations [15]. Interestingly, pharmacogenomic data for older antiretrovirals may have an increased application in developing countries where the availability of newer antiretrovirals is limited. However, in resource-limited settings, confirming genomic studies are just being initiated [16]. Several recent studies have also suggested pharmacokinetic and response differences between men and women that have prompted more detailed investigations in women to determine if dosing adjustment by gender is warranted [17,18]. Based on these early pharmacogenomic research findings, the challenge is now to design large, prospective, randomized protocols to evaluate the clinical impact of predictive genetic testing in HIV pharmacotherapy. This has become more evident with the successful development of CCR5 antagonists based on the genetic characterization of a 32-bp deletion in the CCR5 gene that confers resistance to HIV infection [19]. In August 2007, the US FDA granted accelerated approval for the CCR5 antagonist maraviroc, making it the first approved agent in this drug class. The FDA published a guidance document for submitting pharmacogenomic data in March 2005 that addresses voluntary submission of genomics data for regulatory review [101]. This effort focuses attention on evaluating the potential effectiveness of pharmacogenomic strategies to enhance drug development. Despite many advances in genomic studies of antiretrovirals, the clinical application of pharmacogenomics remains in its infancy. This is mainly due to the fact that few clear relationships between host genotype and patient outcomes have been identified. Two areas of pharmacogenomics that are expected to impact on antiretroviral therapy are polymorphisms associated with metabolism and transport, such as CYP enzymes and membrane transporters, and genetic factors responsible for certain References 1
2
3
4
5
Haas DW. Pharmacogenomics and HIV therapeutics. J. Infect. Dis. 191(9), 1397–1400 (2005).
Morse GD, Catanzaro LM, Acosta EP. Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy. Lancet Infect. Dis. 6(4), 215–225 (2006). Haas DW, Ribaudo HJ, Kim RB et al. Pharmacogenetics of efavirenz and central
www.future-drugs.com
• Dosage individualization of antiretrovirals in clinical practice based on the genotyping of HIV-infected patients and testing for polymorphisms as a means to optimize treatment; • The development of guidelines to address pharmacogenomic applications when considering ethnic variation, particularly in resource-limited settings; • New research based on emerging pharmacogenomic knowledge. It is anticipated that new findings from clinical pharmacogenomic research will facilitate therapeutic individualization and provide better treatment outcomes in HIV-infected patients. Financial & competing interests disclosure
This work was supported in part by grant 5R01DA-015024 from the National Institute on Drug Abuse. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18(18), 2391–2400 (2004). 6
Sadee W, Dai Z. Pharmacogenetics/genomics and personalized medicine. Hum. Mol. Genet. 14(Spec. No. 2), R207–R214 (2005). Fox J, Boffito M, Winston A. The clinical implications of antiretroviral pharmacogenomics. Pharmacogenomics 7(4), 587–596 (2006).
adverse effects, such as HLA-B*5701 for abacavir hypersensitivity. The Roche Diagnostics Amplichip® CYP450 microarray kit has been recently approved by the FDA for clinical screening of common polymorphisms of CYP2D6 and CYP2C19 in psychiatric patients to guide treatment. It seems reasonable to anticipate that, in HIV pharmacotherapy, similar diagnostic tools will be developed to facilitate clinical practice, particularly for CYP2B6 polymorphisms that are central to efavirenz disposition. In addition, the high correlation between HLA-B*5701 and abacavir hypersensitivity may lead to widespread testing to optimize abacavir-containing treatment. The genomic era of HIV pharmacotherapy has been initiated and future success will largely rely on continued translational research in the following key areas:
7
8
Rotger M, Colombo S, Furrer H et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet. Genomics 15(1), 1–5 (2005). Mallal S, Nolan D, Witt C et al. Association between presence of HLAB*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reversetranscriptase inhibitor abacavir. Lancet 359(9308), 727–732 (2002). Martin AM, Nolan D, Gaudieri S et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc. Natl Acad. Sci. USA 101(12), 4180–4185 (2004).
9
Rodriguez Novoa S, Barreiro P, Rendon A et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. Clin. Infect. Dis. 42(2), 291–295 (2006).
10
Rotger M, Taffe P, Bleiber G et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J. Infect. Dis. 192(8), 1381–1386 (2005).
11
Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu. Rev. Pharmacol. Toxicol. 41, 815–850 (2001).
12
Kim RB, Leake BF, Choo EF et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70(2), 189–199 (2001).
7
Ma & Morse
13
14
Ma Q, Brazeau D, Zingman BS et al. Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV. Pharmacogenomics 8(3), 227–235 (2007). Fellay J, Marzolini C, Meaden ER et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359(9300), 30–36 (2002).
15
Phillips EJ. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin. Infect. Dis. 43(1), 103–105 (2006).
16
Maponga CC, Ma Q, Slish JC, Morse GD. HIV pharmacotherapy issues, challenges, and priorities in sub-Saharan African countries. Top. HIV Med. 15(3), 104–110 (2007).
8
17
Ofotokun I, Chuck SK, Hitti JE. Antiretroviral pharmacokinetic profile: a review of sex differences. Gend. Med. 4(2), 106–119 (2007).
18
Umeh OC, Currier JS. Sex differences in pharmacokinetics and toxicity of antiretroviral therapy. Expert Opin. Drug Metab. Toxicol. 2(2), 273–283 (2006).
19
Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382(6593), 722–725 (1996).
Websites 101
US FDA: Guidance for Industry www.fda.gov/cber/gdlns/pharmdtasub.htm
102
HIV pharmacogenomics website www.hiv-pharmacogenomics.org
Affiliations •
Qing Ma University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 243 Fax: +1 716 645 2886 [email protected]
•
Gene D Morse University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 252 Fax: +1 716 645 2886 [email protected]
Expert Rev. Clin. Pharmacol. 1(1), (2008)
Pharmacogenomics and HIV pharmacotherapy ‘The completion of the Human Genome Project has increased the potential of pharmacogenomics to individualize HIV pharmacotherapy based on genetic characterization prior to and during antiretroviral treatment.’ Expert Rev. Clin. Pharmacol. 1(1), 5–8 (2008)
Qing Ma† and Gene D Morse † Author for correspondence University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 243 Fax: +1 716 645 2886 [email protected]
10.1586/17512433.1.1.5
The introduction of pharmacogenomics into toward personalized HIV pharmacotherapy, a HIV pharmacotherapy has provided new paradigm shift from ‘one dosing regimen fits prospects for predicting treatment efficacy all’ to ‘the right regimen for the right patient and the reduction of potential adverse effects. at the right dose and time’ [2]. HIV/AIDS is now considered a serious but There have been significant decreases in treatable chronic infectious disease; however, morbidity and mortality since the implementalong-term viral suppression with current tion of highly active antiretroviral combinaantiretroviral treatment is impacted by tions; however, the perceived need for individadverse drug reactions and drug toxicity, ualization of HIV pharmacotherapy is sometimes leading to reduced medication primarily attributed to the considerable interadherence and the development of viral resist- patient variability in drug exposure to each ance in a significant proportion of patients. antiretroviral component of a combination regThe important role of pharmacogenomics in imen, the subsequent responses and side-effect overcoming these therapeutic challenges is profiles [3]. Traditional approaches utilized for increasingly recognized through the presenta- dose adjustment based on body weight and tion of new clinical and consideration of renal translational research at and/or liver function do not ‘The introduction of HIV/AIDS conferences pharmacogenomics into normalize these interpatient and in recent publications. HIV pharmacotherapy differences. The intrinsic In addition to pharmacopotency of individual has provided new genomic aspects of antiretrovirals and their use antiretroviral metabolism prospects for predicting in potent combination regiand cell membrane trans- treatment efficacy and mens contribute to the port, genetic determinants long-term morbidity that is the reduction of may influence antiviral potential adverse effects.’ associated with HIV pharresponses to HIV pharmamacotherapy in certain cotherapy and long-term outcomes. Screen- patients that respond with more toxicity than ing for the presence of alleles associated with the average patient population. The ability to drug disposition or antiviral responses could identify the genetic factors involved in the drug be utilized to individualize antiretroviral dos- disposition, inadequate response or occurrence ages and to guide the selection of appropriate of adverse effects is the goal of pharmacogealternative therapies [1], providing optimized nomic testing and, with further research, we regimen design and prognostic profiles for should ultimately reduce the unpredictable patient subpopulations. A pharmacogenomics- nature of chronic HIV pharmacotherapy, based treatment approach will represent a step making personalized HIV medicine a reality.
© 2008 Future Drugs Ltd
ISSN 1751-2433
5
Ma & Morse
Pharmacogenomics offers a powerful new tool to investigate variable responses to antiretroviral therapy. The completion of the Human Genome Project has increased the potential of pharmacogenomics to individualize HIV pharmacotherapy based on genetic characterization prior to and during antiretroviral treatment. It has been proposed that therapeutic decisions based on the integration of therapeutic drug monitoring with viral genotyping and phenotyping may be further enhanced by the incorporation of patient genomics [4]. To date, some antiretrovirals have demonstrated a genotype–phenotype correlation (TABLE 1). These correlations have been established for cytochrome P450 (CYP)2B6 and efavirenz disposition [5,6], HLA-B and abacavir hypersensitivity [7,8], and UGT1A1 and atazanavir hyperbilirubinemia [9,10]. However, more research is needed to explore the relationship of polymorphisms, particularly utilizing gene–gene interaction analysis, to investigate pharmacokinetic and pharmacodynamic outcomes. Until these investigations are conducted, the clinical implications of present pharmacogenomic advances should be interpreted with caution. It has been increasingly recognized that genetic differences among ethnic groups may be an important determinant in disease risk, progression, prognosis and response to treatment. In recent years, the research on pharmacogenomic differences among ethnic groups has broadened to include a larger range of targets, such as multiple enzymes that regulate drug metabolism,
cell membrane drug transporters and receptors [11]. Furthermore, increasing evidence suggests that drug metabolism alone does not account for the observed inter-racial variability in drug disposition or response but other processes, such as membrane transport, are also important determinants. Among the drug transporters shown to play a key role in drug disposition, P-glycoprotein encoded by the ABCB1 gene is one of the most extensively studied. The wild-type alleles (CC) of the ABCB1 gene at the 3435C>T locus are more prevalent in the African–American population than in Caucasians and Hispanics [12,13]. Such racial differences in ABCB1 polymorphisms may contribute to previously recognized racial differences in the clinical response to antiretrovirals [14]. In the near future, pharmacogenomics may have the most immediate application in HIV pharmacotherapy with respect to race/ethnicity and sex-related differences in pharmacokinetics and pharmacodynamics. A growing body of literature has highlighted the different distribution of genetic variants among ethnic groups. A recent example is the observed high correlation between HLA-B*5701 genotype and abacavir hypersensitivity, and its rapid evolution toward an application of translational pharmacogenomics. However, the study by Mallal et al. that demonstrated this correlation was conducted primarily in Caucasian males from Australia [7]; therefore, the results from this study are difficult to extrapolate to other ethnicities. Despite recent
Table 1. Genetic polymorphisms that influence the metabolism, transport and toxicity of antiretrovirals*. Gene
SNP
Effect
Confirmation
CYP3A4
Multiple
No effect on nelfinavir or efavirenz
No
CYP3A5
6986A>G
No effect on nelfinavir or efavirenz, higher saquinavir exposure
No
CYP2B6
516G>T
Higher efavirenz exposure and increased toxicity
Yes
CYP2C19
681G>A
Higher nelfinavir exposure and decreased virological failure
No
CYP2D6
Multiple
Trend to higher nelfinavir and efavirenz concentrations
No
3435C>T
Controversial effect on antiretroviral concentrations
No
2677G>T
No effect on efavirenz, protease inhibitors or viral decay
Yes
ABCC1
Multiple
No effect on nelfinavir or efavirenz
No
ABCC2
Multiple
No effect on nelfinavir or efavirenz, increased renal toxicity from tenofovir
No
APOC3/APOE
Multiple
Development of hyperlipidemia
Yes
TNF
238G>A
Development of lipoatrophy
No
HLA-B
HLA-B*57.1
Abacavir hypersensitivity
Yes
HLA-DR
HLA-DRB1*0101
Nevirapine hypersensitivity
No
UGT1A1
UGT1A1*28 UGT1A1*6
Gilbert’s syndrome, hyperbilirubinemia in presence of atazanavir and indinavir
Yes
Metabolism
Transport ABCB1
Toxicity
*
A comprehensive HIV pharmacogenomics reference table is accessible and constantly updated at the HIV pharmacogenomics website [102].
6
Expert Rev. Clin. Pharmacol. 1(1), (2008)
Pharmacogenomics and HIV pharmacotherapy
study findings of a clear relationship between HLA type and abacavir hypersensitivity in white females and Hispanics [8], it remains unclear if screening Asians and African–Americans should be widely accepted, as the prevalence of HLA-B*5701 is less than 1% in these populations [15]. Interestingly, pharmacogenomic data for older antiretrovirals may have an increased application in developing countries where the availability of newer antiretrovirals is limited. However, in resource-limited settings, confirming genomic studies are just being initiated [16]. Several recent studies have also suggested pharmacokinetic and response differences between men and women that have prompted more detailed investigations in women to determine if dosing adjustment by gender is warranted [17,18]. Based on these early pharmacogenomic research findings, the challenge is now to design large, prospective, randomized protocols to evaluate the clinical impact of predictive genetic testing in HIV pharmacotherapy. This has become more evident with the successful development of CCR5 antagonists based on the genetic characterization of a 32-bp deletion in the CCR5 gene that confers resistance to HIV infection [19]. In August 2007, the US FDA granted accelerated approval for the CCR5 antagonist maraviroc, making it the first approved agent in this drug class. The FDA published a guidance document for submitting pharmacogenomic data in March 2005 that addresses voluntary submission of genomics data for regulatory review [101]. This effort focuses attention on evaluating the potential effectiveness of pharmacogenomic strategies to enhance drug development. Despite many advances in genomic studies of antiretrovirals, the clinical application of pharmacogenomics remains in its infancy. This is mainly due to the fact that few clear relationships between host genotype and patient outcomes have been identified. Two areas of pharmacogenomics that are expected to impact on antiretroviral therapy are polymorphisms associated with metabolism and transport, such as CYP enzymes and membrane transporters, and genetic factors responsible for certain References 1
2
3
4
5
Haas DW. Pharmacogenomics and HIV therapeutics. J. Infect. Dis. 191(9), 1397–1400 (2005).
Morse GD, Catanzaro LM, Acosta EP. Clinical pharmacodynamics of HIV-1 protease inhibitors: use of inhibitory quotients to optimise pharmacotherapy. Lancet Infect. Dis. 6(4), 215–225 (2006). Haas DW, Ribaudo HJ, Kim RB et al. Pharmacogenetics of efavirenz and central
www.future-drugs.com
• Dosage individualization of antiretrovirals in clinical practice based on the genotyping of HIV-infected patients and testing for polymorphisms as a means to optimize treatment; • The development of guidelines to address pharmacogenomic applications when considering ethnic variation, particularly in resource-limited settings; • New research based on emerging pharmacogenomic knowledge. It is anticipated that new findings from clinical pharmacogenomic research will facilitate therapeutic individualization and provide better treatment outcomes in HIV-infected patients. Financial & competing interests disclosure
This work was supported in part by grant 5R01DA-015024 from the National Institute on Drug Abuse. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18(18), 2391–2400 (2004). 6
Sadee W, Dai Z. Pharmacogenetics/genomics and personalized medicine. Hum. Mol. Genet. 14(Spec. No. 2), R207–R214 (2005). Fox J, Boffito M, Winston A. The clinical implications of antiretroviral pharmacogenomics. Pharmacogenomics 7(4), 587–596 (2006).
adverse effects, such as HLA-B*5701 for abacavir hypersensitivity. The Roche Diagnostics Amplichip® CYP450 microarray kit has been recently approved by the FDA for clinical screening of common polymorphisms of CYP2D6 and CYP2C19 in psychiatric patients to guide treatment. It seems reasonable to anticipate that, in HIV pharmacotherapy, similar diagnostic tools will be developed to facilitate clinical practice, particularly for CYP2B6 polymorphisms that are central to efavirenz disposition. In addition, the high correlation between HLA-B*5701 and abacavir hypersensitivity may lead to widespread testing to optimize abacavir-containing treatment. The genomic era of HIV pharmacotherapy has been initiated and future success will largely rely on continued translational research in the following key areas:
7
8
Rotger M, Colombo S, Furrer H et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet. Genomics 15(1), 1–5 (2005). Mallal S, Nolan D, Witt C et al. Association between presence of HLAB*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reversetranscriptase inhibitor abacavir. Lancet 359(9308), 727–732 (2002). Martin AM, Nolan D, Gaudieri S et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc. Natl Acad. Sci. USA 101(12), 4180–4185 (2004).
9
Rodriguez Novoa S, Barreiro P, Rendon A et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. Clin. Infect. Dis. 42(2), 291–295 (2006).
10
Rotger M, Taffe P, Bleiber G et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J. Infect. Dis. 192(8), 1381–1386 (2005).
11
Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu. Rev. Pharmacol. Toxicol. 41, 815–850 (2001).
12
Kim RB, Leake BF, Choo EF et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 70(2), 189–199 (2001).
7
Ma & Morse
13
14
Ma Q, Brazeau D, Zingman BS et al. Multidrug resistance 1 polymorphisms and trough concentrations of atazanavir and lopinavir in patients with HIV. Pharmacogenomics 8(3), 227–235 (2007). Fellay J, Marzolini C, Meaden ER et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359(9300), 30–36 (2002).
15
Phillips EJ. Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin. Infect. Dis. 43(1), 103–105 (2006).
16
Maponga CC, Ma Q, Slish JC, Morse GD. HIV pharmacotherapy issues, challenges, and priorities in sub-Saharan African countries. Top. HIV Med. 15(3), 104–110 (2007).
8
17
Ofotokun I, Chuck SK, Hitti JE. Antiretroviral pharmacokinetic profile: a review of sex differences. Gend. Med. 4(2), 106–119 (2007).
18
Umeh OC, Currier JS. Sex differences in pharmacokinetics and toxicity of antiretroviral therapy. Expert Opin. Drug Metab. Toxicol. 2(2), 273–283 (2006).
19
Samson M, Libert F, Doranz BJ et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382(6593), 722–725 (1996).
Websites 101
US FDA: Guidance for Industry www.fda.gov/cber/gdlns/pharmdtasub.htm
102
HIV pharmacogenomics website www.hiv-pharmacogenomics.org
Affiliations •
Qing Ma University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 243 Fax: +1 716 645 2886 [email protected]
•
Gene D Morse University at Buffalo, Pharmacotherapy Research Center, Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Buffalo, NY 14260, USA Tel.: +1 716 645 2828 ext. 252 Fax: +1 716 645 2886 [email protected]
Expert Rev. Clin. Pharmacol. 1(1), (2008)
