International Meta-Analysis of HIV Host Genetics
Thomas R. O’BrienDivision 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• Include all published and unpublished data– Comprehensive– Reduce publication bias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– Reduce technical variability
Purpose
• Synthesize all available data on the effects of CCR5-∆32, CCR2-64I and SDF-1 3’A alleles on HIV-1 disease progression
Genotypic Comparisons
European ancestryCCR5 +/32 & CCR2 +/+CCR5 +/+ & CCR2 64I/+ or 64I/64I CCR5 +/32 & CCR2 64I/+ or 64I/64ICCR5 +/+ & CCR2 +/+
African ancestryCCR2 +/64I or CCR2 64I/64ICCR2 +/+
Both groupsSDF1 3’A/3’ASDF1 3’A/+ or SDF1 +/+
Allele Frequencies:
European ancestryCCR5 32 ~10%CCR2 64I ~10-15%SDF1 3’A ~20%
African ancestryCCR5 32 ~1.7%CCR2 64I ~10-15%SDF1 3’A ~6%
Meta-Analysis Database
• Studies from United States, Europe and Australia
• 1,746 seroconverters from 10 cohorts– 581 AIDS cases– 972 with data on early HIV RNA level
• 2,764 seroprevalent subjects from 12 cohorts
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
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
Standardization of Genotypes
• Not attempted
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
CCR5-32 HeterozygotesRelative Hazard for AIDS
CCR2-64I CarriersRelative Hazard for AIDS
CCR2-64I Carriers Mean Difference in HIV RNA
SDF1 3’A HomozygotesRelative Hazard for AIDS
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
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
CCR5-32 Heterozygotes Mean Difference in HIV RNA
Relative Hazard for AIDSCCR2-64I in Seroconverters
Relative Hazard for AIDSSDF1 3’A/3’A
(Log
sca
le)
CCR5-32 ALLELE
Wild type ATACAGTCAGTATCAATTCTGGAAGAATTTCCAGACATTAAA∆32 ATACA--------------------------------TTAAA