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• Include all published and unpublished data– Comprehensive– Reduce publication bias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