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6 November 2001, Vol 135, No. 9>
Articles | 6 November 2001

Effects of CCR5-Δ 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, MD; Philip S. Rosenberg, PhD; James J. Goedert, MD; Lesley J. Ashton, MPH, PhD; Thomas L. Benfield, MD; Susan P. Buchbinder, MD; Roel A. Coutinho, MD, PhD; Jesper Eugen-Olsen, MSc; Teresa Gallart, MD; Terese L. Katzenstein, MD, PhD; Leondios G. Kostrikis, PhD; Harmjan Kuipers, MSc; Leslie G. Louie, MPH, PhD; Simon A. Mallal, MBBS, FRACP; Joseph B. Margolick, MD, PhD; Olga P. Martinez, MBBS, FRACP; Laurence Meyer, MD, PhD; Nelson L. Michael, MD, PhD; Eva Operskalski, PhD, MBA; Giusseppe Pantaleo, MD; G. Paolo Rizzardi, MD; Hanneke Schuitemaker, PhD; Haynes W. Sheppard, PhD; Graeme J. Stewart, MD, PhD; Ioannis D. Theodorou, MD, PhD; Henrik Ullum, MD, PhD; Elisa Vicenzi, PhD; David Vlahov, PhD; David Wilkinson, PhD; Cassy Workman, MBBS; Jean-Francois Zagury, MD, PhD; Thomas R. O'Brien, MD, MPH, International Meta-Analysis of HIV Host Genetics
[+] Article and Author Information

From University of Ioannina School of Medicine, Ioannina, Greece; National Cancer Institute, National Institutes of Health, Bethesda, Maryland; National Center in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Hvidovre Hospital, Copenhagen, Denmark; San Francisco Department of Public Health, San Francisco, California; Municipal Health Service Amsterdam, Department of Public Health and Environment, Amsterdam, the Netherlands; Hospital Clinic Universitari, Barcelona, Spain; Rigshospitalet, Copenhagen, Denmark; Aaron Diamond AIDS Research Center, New York, New York; HIV R&D Group, Australian Red Cross Blood Service, Sydney, Australia; Children's Hospital Oakland Research Institute, Oakland, California; Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Hopital de Bicetre, Le Kremlin–Bicetre, France; Walter Reed Army Institute of Research, Rockville, Maryland; University of Southern California, Los Angeles, California; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Central Laboratory of the Netherlands Red Cross Transfusion Service, Amsterdam, the Netherlands; California Department of Health Services, Berkeley, California; Westmead Hospital, Westmead, Australia; Laboratoire d'Immunologie Cellulaire et Tissulaire, Hôpital Pitié-Salpêtrière, Paris, France; San Raffaele Scientific Institute, Milan, Italy; University of Texas Southwestern Medical Center, Dallas, Texas; AIDS Research Initiative, Darlinghurst, Australia; and Université Pierre et Marie Curie, Paris, France.


Acknowledgments: The authors thank Franklin J. Demuth for assistance with data management and Jennifer L. Martin and Julie Russell Grey for logistical support.

Requests for Single Reprints: Thomas R. O'Brien, MD, MPH, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 8016, Rockville, MD 20852; e-mail, obrient@exchange.nih.gov.

Current Author Addresses: Dr. Ioannidis: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.

Drs. Rosenberg, Goedert, and O'Brien: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Bethesda, MD 20852.

Dr. Ashton: National Center in HIV Epidemiology and Clinical Research, 376 Victoria Street, Sydney NSW 2010, Australia.

Dr. Benfield: Department of Infectious Diseases, Hvidovre Hospital, Kettegaard Alle, 30, Hvidovre, DK-2650, Denmark.

Dr. Buchbinder: HIV Research Section, San Francisco Department of Public Health, 25 Van Ness Avenue, #500, San Francisco, CA 94102-6033.

Dr. Coutinho: Municipal Health Service Amsterdam, Department of Public Health and Environment, Nieuwe Achtergracht 100, 1018 WT Amsterdam, the Netherlands.

Dr. Eugen-Olsen: Clinical Research Unit, Department 441, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.

Dr. Gallart: Servei d'Immunologia, Hospital Clinic, Villaroel, 170, 08036 Barcelona, Spain.

Drs. Katzenstein and Ullum: Department of Infectious Diseases and Department of Clinical Immunology, Rigshospitalet, Blegdamsvej 9, Copenhagen E, DK-2100, Denmark.

Dr. Kostrikis: Department of Hygiene and Epidemiology, Athens University Medical School, Mikras Asias 75, Athens 11527, Greece.

Dr. Kuipers: Erasmus University, OR Molewater Plein 50, 3015 GE Rotterdam, the Netherlands.

Dr. Louie: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673.

Drs. Mallal and Martinez: Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Wellington Street, Perth, Western Australia 6000.

Dr. Margolick: Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.

Dr. Meyer: Service d'Epidemiologie-INSERM U292, Hopital de Bicetre, 82 rue du general Leclerc, 94276 Le Kremlin-Bicetre Cedex, France.

Dr. Michael: Division of Retrovirology, Walter Reed Army Institute of Research, 1600 East Gude Drive, Rockville, MD 20850.

Dr. Operskalski: Department of Medicine, University of Southern California, 1640 Marengo Street, Los Angeles, CA 90033.

Drs. Pantaleo and Rizzardi: Centre Hospitalier Universitaire Vaudois, rue du Bugnon, 1005 Lausanne, Switzerland.

Dr. Schuitemaker: Department of Clinical Viro-Immunology, Central Laboratory of the Netherlands Red Cross Transfusion Service, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.

Dr. Sheppard: California Department of Health Services, 850 Marina Bay Parkway, Richmond, CA 94804.

Dr. Stewart: Department of Clinical Immunology, Westmead Hospital, Westmead NSW 2145, Australia.

Dr. Theodorou: INSERM u543, Bâtiment CERVI Hôpital de la Pitié Salpêtrière, 83 Boulevard de l'Hôpital, 75013 Paris, France.

Dr. Vicenzi: San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.

Dr. Vlahov: New York Academy of Medicine, 1216 5th Avenue, New York, NY 10029.

Dr. Wilkinson: Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8LS, Canada.

Dr. Workman: AIDS Research Initiative, Box 306, Sydney NSW 1300, Australia.

Dr. Zagury: Laboratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, 4 Place Jussieu-Tour 32 −B.P. 198, 75252 Paris, Cedex 05, France.

Author Contributions: Conception and design: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, R.A. Coutinho, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, H. Kuipers, S.A. Mallal, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, E. Vicenzi, D. Wilkinson, J.-F. Zagury, T.R. O'Brien.

Analysis and interpretation of the data: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, J. Eugen-Olsen, J.B. Margolick, L. Meyer, N.L. Michael, T.R. O'Brien.

Drafting of the article: J.P.A. Ioannidis, P.S. Rosenberg, J.B. Margolick, N.L. Michael, I.D. Theodorou, T.R. O'Brien.

Critical revision of the article for important intellectual content: P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, L.G. Louie, S.A. Mallal, J.B. Margolick, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, H. Ullum, E. Vicenzi, D. Vlahov, D. Wilkinson, J.-F. Zagury, T.R. O'Brien.

Final approval of the article: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Kostrikis, H. Kuipers, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, H. Schuitemaker, H.W. Sheppard, G.J. Stewart, I.D. Theodorou, H. Ullum, E. Vicenzi, D. Vlahov, D. Wilkinson, C. Workman, J.-F. Zagury, T.R. O'Brien.

Provision of study materials or patients: J.J. Goedert, L.J. Ashton, T.L. Benfield, S.P. Buchbinder, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, G. Pantaleo, G.P. Rizzardi, I.D. Theodorou, H. Ullum, D. Vlahov, D. Wilkinson, C. Workman.

Statistical expertise: J.P.A. Ioannidis, P.S. Rosenberg, D. Vlahov.

Obtaining of funding: J.J. Goedert, L.G. Kostrikis, L. Meyer, H. Ullum, D. Vlahov, T.R. O'Brien.

Collection and assembly of data: J.P.A. Ioannidis, P.S. Rosenberg, J.J. Goedert, L.J. Ashton, T.L. Benfield, R.A. Coutinho, J. Eugen-Olsen, T. Gallart, T.L. Katzenstein, L.G. Louie, S.A. Mallal, J.B. Margolick, O.P. Martinez, L. Meyer, N.L. Michael, E. Operskalski, H. Schuitemaker, H. Ullum, D. Vlahov, C. Workman, T.R. O'Brien.


Ann Intern Med. 2001;135(9):782-795. doi:10.7326/0003-4819-135-9-200111060-00008
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The burgeoning information on the human genome creates opportunities and challenges for studies of disease associations. Because genetic differences often produce modest effects, many patients must be studied to reach definitive conclusions. In the absence of a single large study, meta-analysis of individual-patient data (1 - 3) from smaller studies offers a way to assemble an adequate sample size. This approach is based on a unifying protocol that has standardized analytic definitions. When the protocol is applied to data contributed by most investigators working in a field, this method can provide more convincing results than a simple pooling of data or a meta-analysis of published reports (3). A meta-analysis of individual-patient data is also superior to a meta-analysis of published reports for examining differences in reported results.

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Figure 1.
Meta-analysis of the effect ofCCR5-Δ 32heterozygosity on HIV-1 disease progression among patients of European descent.

In each panel, patients who are heterozygous for CCR5-Δ 32 without CCR2-64I are compared with patients who are homozygous for wild-type CCR5 and CCR2. Shown are the relative hazard for AIDS from seroconversion (A) or study entry (B); relative hazard for death following the development of AIDS (C, D); and mean difference in log10HIV-1 RNA levels at 6 to 42 months after seroconversion (E) or at first study measurement (F). Hazard ratios in panels A through D are plotted on a natural log scale. Relative hazard = 1 (dotted line) indicates no difference in hazard rates; values less than 1 indicate relative protection for CCR5-Δ 32 carriers. For each cohort, point estimates (boxes) and 95% CIs (bars) are provided. Within panels, the areas of the boxes are proportional to the weights used in meta-analytic synthesis. The glyphs labeled “Synthesis” (diamonds) show the results of meta-analysis; the center lines indicate summary estimates, and the length of the diamonds spans the 95% CI, which was based on a random-effects model. Cohort-specific results are overlaid on a shaded line and band that correspond to the summary estimate and CI, respectively. Heterogeneity of the study-specific results was measured by using the Q statistic: A, P > 0.2; B, P = 0.11; C, P > 0.2; D, P = 0.15; E, P > 0.2; F, P = 0.05. Each Q statistic has a chi-square distribution with the degrees of freedom equal to one less than the number of cohorts in the analysis. Only seroconverter groups and seroprevalent groups with relevant data for at least 20 patients are shown. ACHM = Amsterdam Cohort of Homosexual Men; AIVD = Amsterdam Cohort of Intravenous Drug Users; ARI = AIDS Research Initiative (Australia); CAC = Copenhagen AIDS Cohort; DCG = District of Columbia Gay Cohort; HGDS = Hemophilia Growth and Development Study; MACS-Eur = patient subgroup of European descent in Multicenter AIDS Cohort Study; MHCS-Eur = patient subgroup of European descent in Multicenter Hemophilia Cohort Study; SEROCO = French Seroconverter Cohort; SFCC = San Francisco City Clinic Cohort; SFMHS = San Francisco Men's Health Study; SHCS = Swiss HIV Cohort Study.

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Figure 2.
Meta-analysis of the effect of theCCR2-64Iallele on HIV-1 disease progression.

Each panel compares patients who are homozygous or heterozygous (but without the CCR5-Δ 32 allele) for CCR2-64I with patients who are homozygous for wild-type CCR5 and wild-type CCR2. The panels are constructed as described in the legend for Figure 1. The Q statistic was used to calculate P values: A, P > 0.2; B, P > 0.2; C, P = 0.10; D, P > 0.2; E, P > 0.2; F, P > 0.2. Subgroups comprising patients of European (Eur) or African (Afr) ancestry are noted. Otherwise, cohorts are limited to patients of European descent. Only seroconverter and seroprevalent groups with relevant data for at least 20 patients are shown. ACHM = Amsterdam Cohort of Homosexual Men; AIVD = Amsterdam Cohort of Intravenous Drug Users; ALIVE = AIDS Link to the Intravenous Experience; ARI = AIDS Research Initiative (Australia); CAC = Copenhagen AIDS Cohort; DCG = District of Columbia Gay Cohort; HGDS = Hemophilia Growth and Development Study; MACS = Multicenter AIDS Cohort Study; MHCS = Multicenter Hemophilia Cohort Study; SEROCO = French Seroconverter Cohort; SFCC = San Francisco City Clinic Cohort; SFMHS = San Francisco Men's Health Study; SHCS = Swiss HIV Cohort Study.

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Figure 3.
Meta-analysis of the effect ofSDF-1 3′Ahomozygosity on HIV-1 disease progression among patients of European descent.

Unless otherwise specified, the panels were constructed as described in the legend for Figure 1. Each panel compares patients homozygous for SDF-1 3′A with all other patients; the seroconverter and seroprevalent groups shown are those that contributed usable data on ≥ 20 patients. The six panels show the relative hazard for AIDS from seroconversion (A) or from study entry (B), the relative hazard for death (C, D), and, finally, the relative hazard for death following the development of AIDS (E, F). The P values for the Q statistics were: A, P = 0.02; B, P > 0.2; C, P = 0.01; D, P > 0.2; E, P = 0.01; F, P > 0.2. ACHM = Amsterdam Cohort of Homosexual Men; CAC = Copenhagen AIDS Cohort; CHIC = Copenhagen HIV Immunology Cohort; DCG = District of Columbia Gay Cohort; HGDS = Hemophilia Growth and Development Study; MACS-Eur = patient subgroup of European descent in Multicenter AIDS Cohort Study; MHCS-Eur = patient subgroup of European descent in Multicenter Hemophilia Cohort Study; SEROCO = French Seroconverter Cohort; SFCC = San Francisco City Clinic Cohort; SFMHS = San Francisco Men's Health Study; SHCS = Swiss HIV Cohort Study.

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Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general jounals
BMJ 2010;341:c5893-c1494.

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Summary for Patients

Genes and HIV Progression

The summary below is from the full report titled “Effects of CCR5-Δ32, CCR2-64I, and SDF-1 3′A Alleles on HIV-1 Disease Progression: An International Meta-Analysis of Individual-Patient Data.” It is in the 6 November 2001 issue of Annals of Internal Medicine (volume 135, pages 782-795). The authors are JPA Ioannidis, PS Rosenberg, JJ Goedert, LJ Ashton, TL Benfield, SP Buchbinder, RA Coutinho, J Eugen-Olsen, T Gallart, TL Katzenstein, LG Kostrikis, H Kuipers, LG Louie, SA Mallal, JB Margolick, OP Martinez, L Meyer, NL Michael, E Operskalski, G Pantaleo, GP Rizzardi, H Schuitemaker, HW Sheppard, GJ Stewart, ID Theodorou, H Ullum, E Vicenzi, D Vlahov, D Wilkinson, C Workman, J-F Zagury, and TR O'Brien, for the International Meta-Analysis of HIV Host Genetics.

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