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Will Pharmacogenomic Discoveries Improve HIV Therapeutics

Objectives. To provide a brief introduction to human genetics.To provide an overview of current knowledge regarding human genetic variability and responses to HIV therapy.To suggest future directions for HIV pharmacogenomics.. . Slide

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Will Pharmacogenomic Discoveries Improve HIV Therapeutics

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    2. Objectives To provide a brief introduction to human genetics. To provide an overview of current knowledge regarding human genetic variability and responses to HIV therapy. To suggest future directions for HIV pharmacogenomics.

    3. Genetic Variants Polymorphism: a common DNA variant (>1% of population) Base substitution, deletion, or insertion. Most common are Single Nucleotide Polymorphisms (SNP). May be in coding or non-coding region. Alter amino acid (non-synonymous) or not (synonymous). May alter function or expression level of protein. Mutation: a rare DNA variant (<<1% of population) Points: To explain some basic of genetic variability, SNPs, and other terms.Points: To explain some basic of genetic variability, SNPs, and other terms.

    4. Haplotypes and Linkage Disequilibrium Certain SNPs tend to be inherited together = LINKAGE DISEQUILIBRIUM Points: To explain concepts of haplotype and LD. In a population, some combination much more common than chance = LD.Points: To explain concepts of haplotype and LD. In a population, some combination much more common than chance = LD.

    5. The Challenge of Genome SNP Scanning The human genome = 3 billion base pairs. About 1 SNP per 1,000 base pairs. = about 3 million SNPs per person. Cost for genome scan = 5 to 10 cents per SNP. Cost for total genome SNP scan = $150,000 to $300,000 per person. Can reduce cost by: Scanning only coding regions. Scanning only non-synonymous SNPs. Taking advantage of linkage disequilibrium. Points: At present, cost prohibits genome-wide scanning,. Cost is coming down. There are strategies to reduce cost.Points: At present, cost prohibits genome-wide scanning,. Cost is coming down. There are strategies to reduce cost.

    6. Reaction Drugs Gene Hypersensitivity Abacavir HLA-B*5701, hsp70-hom (Lancet 2002:359,727 & 1121; PNAS 2004:101,4180) Hyperbilirubinemia Indinavir, UGT-1A1 (Gilbert’s) Atazanavir (PNAS 2001:98,12671; ICAAC 2002) Lipoatrophy NRTI TNF-a promoter (AIDS 2002:16,2013; AIDS 2003:17,121) Rash/Hepatitis/Fever Nevirapine HLA-DRB1*01 (AIDS 2005:19,97) Associations between Allelic Variants and HIV Treatment Response

    7. Host Genetics and Efavirenz Introduction Efavirenz (EFV) is the most commonly prescribed initial therapy for HIV-1 infection in the US. CNS side effects are common with EFV EFV plasma clearance is slower in blacks than in whites. (Barrett 2002, Pfister 2003, Ribaudo 2004) One study suggested earlier virologic failure on EFV in blacks than in whites. (Wegner 2002) Another study showed earlier treatment failure in Hispanics but not in blacks or whites. (Lupo 2002)

    8. Efavirenz Metabolism by CYP2B6

    9. Host Genetics and Efavirenz Methods Study Design and Subjects Eligible subjects were previously randomized to receive EFV in A5095/A5097s. A5095 randomized 1,147 ART-naďve subjects to EFV (600 mg QD), abacavir, or both, with AZT and 3TC. EFV and abacavir were double-blinded. A5097s characterized EFV CNS adverse effects and pharmacokinetics. 202 of the 303 A5097s participants were randomized to EFV.

    10. Host Genetics and Efavirenz: ACTG studies (A5095/5097s) Efavirenz Levels EFV plasma levels were greater in blacks and Hispanics than in whites (Ribaudo et al, 11th CROI). Median EFV AUC0-24h Blacks 58 ľgˇhrˇmL-1 Hispanics 66 ľgˇhrˇmL-1 Whites 46 ľgˇhrˇmL-1 (overall P ? 0.001 for all comparisons) There was much overlap in the distribution of PK parameters between racial/ethnic populations.

    15. Host Genetics and Efavirenz Conclusions An exon 4 CYP2B6 SNP that was more common in blacks than in whites was associated with higher EFV plasma levels, and CNS adverse experiences. Blacks DID NOT have more CNS side effects. The association with exon 4 SNP was unexpected based on prior studies of CYP2B6. CYP3A4 and CYP3A5 SNPs may also be weakly associated with EFV levels.

    16. Nevirapine Liver Toxicity Nevirapine (NVP) can cause hepatotoxicity. NVP is metabolized by CYP2B6, not known to be a substrate for P-glycoprotein. In a study in South Africa (FTC-302), grade 3 or 4 LFT elevations affected 66 (17%) NVP recipients. We explored MDR1, CYP2B6, CYP3A4, and CYP3A5 SNPs and NVP hepatotoxicity. Two matched controls identified for each case.

    17. Baseline Characteristics of Study Subjects

    18. MDR1 Polymorphism and Nevirapine Hepatotoxicity: FTC-302 and ACTG Collaboration “Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult“Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult

    19. Tissue Distribution of P-glycoprotein “Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult“Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult

    20. Study Design and Subjects ACTG 384 enrolled subjects Oct ‘98 to Nov ‘99, with up to 3-year follow-up ACTG 384 randomized 980 ART-naďve subjects to EFV (600 mg QD), NFV (1250 mg BID), or both, with AZT/3TC or ddI/d4T EFV and NFV were double-blinded Pharmacogenetics of Efavirenz and Nelfinavir Methods

    22. Multivariate Logistic Regression Model of Failure with Genotypic NNRTI Resistance among Subjects Randomized to EFV (MDR1 3435C>T)

    23. Peripheral Neuropathy in ACTG 384 “Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult“Lipodystrophy” is an umbrella term used to describe HIV-associated metabolic disorders and fat redistribution. It more correctly describes some types of fat maldistribution experienced by some patients with this syndrome. It may not adequately describe a constellation of symptoms seen in some patients The lack of a standard case definition may skew study results and make it impossible to compare certain studies. Additionally, the confusion surrounding the definition of “lipodystrophy” may make diagnosis more difficult

    24. Mitochondrial Haplogroups Some heritable mutations have reached polymorphic frequencies Haplogroups defined by patterns of polymorphisms 9 European haplogroups H, I, J, K, T, U, V, W, X Haplogroup J associated with longevity, protection from Parkinson disease

    25. Mitochondrial Haplogroups and Neuropathy European haplogroup frequencies (ACTG 384)

    26. Mitochondrial Haplogroups and Neuropathy: Multivariate logistic regression model

    27. Conclusions Associations between genetics and HIV treatment responses are increasingly being discovered. Knowledge of genotypes may allow us to: Better individualize prescribing. Better design clinical trials. Anticipate likelihood of complications in different populations worldwide. Identify targets for new therapeutics.

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