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International Meta-Analysis of HIV Host Genetics

International Meta-Analysis of HIV Host Genetics. Thomas R. O’Brien Division of Cancer Epidemiology and Genetics October 6, 2005. Meta Analysis of Individual Patient Data. Include all published and unpublished data Comprehensive Reduce publication bias Standardized protocol

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International Meta-Analysis of HIV Host Genetics

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  1. International Meta-Analysis of HIV Host Genetics Thomas R. O’Brien Division of Cancer Epidemiology and Genetics October 6, 2005

  2. Meta Analysis of Individual Patient Data • Include all published and unpublished data • Comprehensive • Reduce publication bias • Standardized protocol • Reduce technical variability

  3. Purpose • Synthesize all available data on the effects of CCR5-∆32, CCR2-64I and SDF-1 3’A alleles on HIV-1 disease progression

  4. Genotypic Comparisons • European ancestry • CCR5 +/32 & CCR2 +/+ • CCR5 +/+ & CCR2 64I/+ or 64I/64I • CCR5 +/32 & CCR2 64I/+ or 64I/64I • CCR5 +/+ & CCR2 +/+ • African ancestry • CCR2 +/64I or CCR2 64I/64I • CCR2 +/+ • Both groups • SDF1 3’A/3’A • SDF1 3’A/+ or SDF1 +/+ • Allele Frequencies: • European ancestry • CCR5 32 ~10% • CCR2 64I ~10-15% • SDF1 3’A ~20% • African ancestry • CCR532 ~1.7% • CCR2 64I ~10-15% • SDF1 3’A ~6%

  5. Meta-Analysis Database • Studies from United States, Europe and Australia • 1,746 seroconverters from 10cohorts • 581 AIDS cases • 972 with data on early HIV RNA level • 2,764 seroprevalent subjects from 12 cohorts

  6. Standardization of Data • Seroconverters • Seroconversion defined as mid-point between the last HIV-1-negative and first HIV-1-positive visit • Both specimens obtained after enrollment in prospective cohort • Seroprevalent subjects • Time-scale originating at date of study entry • Follow-up censored as of January 1, 1996 • Communications between coordinating center and contributing investigators to verify that data adhered to common definitions of the meta-analysis

  7. Standardization of Phenotypes • AIDS • 1987 CDC definition • Death • HIV-1 RNA level • Consistent lab method and specimen (serum or plasma) within each study • Measured 6 to 42 months after seroconversion

  8. Standardization of Genotypes • Not attempted

  9. Effects of CCR5-32, CCR2-64I and SDF-1 3’A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data JOHN P.A. IOANNIDIS, PHILIP S. ROSENBERG, JAMES J. GOEDERT, LESLEY J. ASHTON, SUSAN P. BUCHBINDER, ROEL A. COUTINHO, JESPER EUGEN-OLSEN, TERESA GALLART, TERESE L. KATZENSTEIN, LEONDIOS G. KOSTRIKIS, HARMJAN KUIPERS, LESLIE LOUIE, SIMON A. MALLAL, JOSEPH B. MARGOLICK, OLGA P. MARTINEZ, LAURENCE MEYER, NELSON L. MICHAEL, STEPHEN J. O’BRIEN, EVA OPERSKALSKI, GIUSSEPPE PANTALEO, G. PAOLO RIZZARDI, HANNEKE SCHUITEMAKER, HAYNES W. SHEPPARD, MICHAEL W. SMITH, GRAEME J. STEWART, IOANNIS D. THEODOROU, HENRIK ULLUM, ELISA VICENZI, DAVID VLAHOV, DAVID WILKINSON, CASSY-WORKMAN, JEAN-FRANCOIS ZAGURY, and THOMAS R. O'BRIEN for the INTERNATIONAL META-ANALYSIS of HIV HOST GENETICS Ann Intern Med, 2001

  10. CCR5-32 HeterozygotesRelative Hazard for AIDS

  11. CCR2-64I CarriersRelative Hazard for AIDS

  12. CCR2-64I CarriersMean Difference in HIV RNA

  13. SDF1 3’AHomozygotesRelative Hazard for AIDS

  14. Summary • Both CCR5-32 and CCR2-64I • Confer ~25% reduction in the risk of AIDS • Associated with significantly lower HIV RNA • No consistent evidence of protection for SDF1-3’A/3’A

  15. HIV-1 Meta-Analyses • Meta-analysis of individual participants' data in genetic epidemiology Am J Epidemiol, 2002 • Effects of CCR5-∆32 & CCR2-64I alleles on HIV-1 disease progression: The protection varies with duration of infection AIDS, 2003 • Effect of CCR5-Δ32 heterozygosity on the risk of perinatal HIV-1 infection: a meta-analysis JAIDS, 2003 • Effects of CCR5- Δ32 and CCR2 64I alleles on disease progression of perinatally HIV-infected children: an international meta-analysis AIDS, 2003

  16. CCR5-32 HeterozygotesMean Difference in HIV RNA

  17. Relative Hazard for AIDS CCR2-64I in Seroconverters

  18. Relative Hazard for AIDS SDF1 3’A/3’A (Log scale)

  19. CCR5-D32 ALLELE Wild typeATACAGTCAGTATCAATTCTGGAAGAATTTCCAGACATTAAA ∆32ATACA--------------------------------TTAAA

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