Pharmacogenomics of HIV Therapy

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

3. Yes 2. No 3. Unsure 4. I don�t order tests, so this doesn�t apply to me Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

4. Yes 2. No 3. Unsure Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

5. Human Chromosomes map in the back of epi update map in the back of epi update

6. The four DNA bases Adenosine Cytosine Thymine Guanine

7. 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.

8. 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.

9. Caveat of Genetic Association Studies

10. Some ARV Pharmacogenetic Variants Abacavir HSR (HLA-B*5701) white > black Efavirenz PK (CYP2B6) black > white Nevirapine LFTs (ABCB1) black > white Atazanavir jaundice (UGT) white > black Atazanavir PK (PXR?) white > black Nelfinavir (CYP2C19) Asian > black, white 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.

11. Abacavir hypersensitivity&HLA-B*5701 Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

14. DHHS Panel Guidelines (12/07)(http://aidsinfo.nih.gov) �The Panel recommends HLA-B*5701 testing prior to initiating abacavir therapy... HLA-B*5701-positive patients should not be prescribed abacavir�, positive status should be recorded as an abacavir allergy in the patient�s medical record�.�

16. Drug Metabolism and Elimination

18. Efavirenz&CYP2B6 Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

20. Efavirenz Metabolism by CYP2B6

21. Host Genetics and Efavirenz:ACTG studies (A5095/5097s) Efavirenz Levels EFV plasma levels were greater in blacks than in whites (Ribaudo et al, 11th CROI). Median EFV AUC0-24h Blacks 58 �g�hr�mL-1 Whites 46 �g�hr�mL-1 Much overlap in the distribution of PK parameters between racial/ethnic populations.

23. map in the back of epi update map in the back of epi update

24. Efavirenz CNS Side Effects Genotype can�t reliably predict CNS side effects� Most patients with CNS side effects don�t have high EFV levels. Most patients with high EFV levels don�t have bad CNS side effects.

26. Pharmacogenetics of NNRTIs in African Americans(Vanderbilt-Meharry CFAR project)

30. Nevirapine&CYP2B6, ABCB1, HLA Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

31. Nevirapine Hypersensitivity & HLA-DRB1*0101Martin et al AIDS 2005:19,93

32. Nevirapine Hypersensitivity & Other HLA�s Sardiniaa 13 with nevirapine HSR, 36 without HSR 46% with HSR had HLA-Cw8 5% without HSR had HLA-Cw8 (P = 0.004) Japanb 12 with nevirapine HSR, 29 without HSR 42% with HSR had HLA-Cw8 10% without HSR had HLA-Cw8 (P = 0.03) Thailandc HLA�B*3505 predicts skin rash (OR � 20-39) Replicated in 2 cohorts.

33. 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

34. Nevirapine Liver Toxicity In a study in South Africa (FTC-302), grade 3 or 4 LFT elevations affected 66 (17%) NVP recipients. We explored ABCB1, CYP2B6, CYP3A4, and CYP3A5 SNPs and NVP hepatotoxicity. Two matched controls identified for each case. 53 cases & 108 matched controls

35. MDR1 (ABCB1) 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

36. map in the back of epi update map in the back of epi update

37. Pharmacogenetics of Nevirapine Hepatotoxicity: Mozambique 161 pregnant women initiating ART. 73 NVP hepatotoxicity cases 88 controls 6 SNPs in MDR1, CYP2B6, CYP3A4, CYP3A5. (ABCB1) MDR1 3435C>T associated with hepatotoxicity (p=0.03, OR=2.3). T allele protective.

38. Atazanavir&UGT1A1, PXR Points: 1. Inherited variability in drug response appreciated for 50 years.Points: 1. Inherited variability in drug response appreciated for 50 years.

41. Drug Metabolism and Elimination

43. Drug Phenotype Gene Abacavir Hypersensitivity HLA-B*5701 Lancet 2002:359,727 & 1121; PNAS 2004:101,4180 Indinavir Jaundice UGT-1A1 Atazanavir PNAS 2001:98,12671; ICAAC 2002; JID 2005;192,1381 NRTI Lipoatrophy TNF-a promoter, HFE AIDS 2002:16,2013; AIDS 2003:17,121; JID 2008:197, 858 Nevirapine Hypersensitivity HLA-DRB1*0101, -Cw8, -B3505 Hepatotoxicity ABCB1 Pharmacokinetics CYP2B6 AIDS 2005:19,97; Pharmacogenet Genom 2005;15,1; Clin Inf Dis 2006;43,779 & 783; AIDS 2006:20,1621; AIDS 2007;21,264; Pharmacogenet Genom 2009;19,139 Associations Between Allelic Variants and HIV Treatment Response

44. Drug Phenotype Gene Efavirenz CNS effects, Pharmacokinetics CYP2B6 Viral response, Resistance ABCB1, CYP2A6 Lancet 2002;359:30; AIDS 2004;18:2391; Pharmacogenet Genom 2005;15:1; JID 2005;192:1931; CID 2006;42:401; CROI 2008; JID 2009;199:872 Nelfinavir Viral response, Pharmacokinetics CYP2C19 JID 2005;192:1931 PIs Dyslipidemia APOC, RETN JID 2005;191:1419; PLoS Med 2006;3:e52; AIDS 2008;22:1561. NRTIs Peripheral neuropathy Mitochondrial AIDS 2005;19:1341, AIDS 2006;20:1503 haplogroup T, HFE HAART CD4 recovery Proliferation & JID 2006;194:1098 apoptosis Genetic Associations (continued)

45. Drug Phenotype Gene Tenofovir Renal toxicity MRP2 (ABCC2) JID 2006;94:1481 Others� ? ? ? ? ? ? ? Genetic Associations (continued)

46. Approved Studies with ACTG Human DNA from US (A5128) Project Papers NWCS 213 � efavirenz, nelfinavir PK & response ? 2 NWCS 214 � efavirenz CNS toxicity and PK ? 2 NWCS 215 � T cell turnover rates ? 1 NWCS 224 � metabolic complications 1 NWCS 233 � CD4 increase on ART ? 1 NWCS 237 � metabolic complications * NWCS 238 � peripheral neuropathy ? 3 NWCS 239 � efavirenz resistance after Rx interruption ? 1 NWCS 243 � HLA and viral evolution * NWCS 248 � efavirenz & lopinavir PK 1 NWCS 253 � efavirenz response ? NWCS 254 � efavirenz response ? NWCS 256 � peripheral neuropathy ? NWCS 259 � metabolic complications NWCS 262 � innate immunity and responses to ART NWCS 266 � treatment responses to ART NWCS 268 � efavirenz PK ? NWCS 273 � peripheral neuropathy ? NWCS 275 � pharmacogenomics of HIV therapy ? NWCS 279 � immune control NWCS 280 � lipoatrophy ? NWCS 291 � tenofovir renal toxicity ? NWCS 293 � protease inhibitor PK and response ? NWCS 301 � efavirenz PK and treatment response ? 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.