DOSSIER Web site: Prepared by CAMACS Fax: May 2011 The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI

MACS Founding Principal Investigators Sites: Baltimore, MD - Frank Polk Chicago, IL - John Phair Los Angeles, CA - Roger Detels Pittsburgh, PA - Charles Rinaldo Data Coordinating Center Data Center – Alvaro Muñoz November 2004

MACS Sites and Principal Investigators  Sites: Baltimore, MD (J. Margolick) Chicago, IL (J. Phair, S. Wolinsky) Los Angeles, CA (R. Detels, O. Martinez- Maza) Pittsburgh (C. Rinaldo, L. Kingsley)  Data Coordinating Center (CAMACS): Baltimore, MD (L. Jacobson, A. Muñoz) November 2004

MACS Working Groups  Behavioral (D. Ostrow)  Biomarker (C. Rinaldo)  Cardiovacular (W. Post)  Clinical (F. Palella)  Core Laboratory (A. Butch)  Data (L. Jacobson)  Genetics (S. Wolinsky) August 2010  Hepatitis (C. Thio)  Malignancy/Pathology (O. Martinez-Maza)  Metabolic (L. Kingsley)  Neuropsychology (E. Miller)  Renal (F. Palella)  Viral Immune Pathogenesis (J. Margolick)

Semiannual Visit  Questionnaire / ACASI Medical History, Health Services, Behavior Medications: Antiretrovirals, OI- specific, Adherence  Labs T-cells, HIV RNA, HBV & HCV serology Lipids, liver and kidney function tests / anal cytology  Banked Specimens Plasma, Serum, Cells B-cell lines PBMC pellets May 2009  Demographics  Physical Examination / Lipodystrophy / Frailty  Psychosocial Quality of Life (SF36) Depression (CESD) Activities of Daily Living (IADL)  Neuropsychological Screening

Continuous Outcome Ascertainment  Seroconversion  Clinical Outcomes (medical records confirmation) AIDS diagnoses Non-AIDS diagnoses  Cardiovascular disease  Cerebrovascular disease  Kidney disease  Liver disease  Lung infection, bacterima, septicemia  Malignancies  Neurologic Mortality November 2004

CAMACS  Planning and design of studies  Coordination of data acquisition Form development Codebooks Data transfer  Standardization and data management Edits and updates Data security  Data analysis, statistical computing and methodological research September 1995

MACS Database (as of May 2011) May 2011 Publications ( published & in press ) 1,195 Participants 6,972 Person-Years 86,883 Variables 8,920 Repository aliquots 1,490,995 (plasma, serum, cells, urine) HIV+ HIV- Person-Visits56,352 72,566 CD4 Measurements51,798 57,808 HIV RNA Measurements34,149 1,206

MACS Subgroups of Particular Interest  Long-term seropositive individuals with minimal declines in CD4 levels  Seropositive individuals with rapid declines in CD4 levels  Long-term survivors with low CD4 levels  Seroconverters  High-risk seronegatives  Seropositives on treatment  >55 years old

Strengths of the MACS  Comparison groups of similar risk HIV-infected not receiving treatment Uninfected persons  Standardized, complete longitudinal data collected with uniform frequency, before and after treatment Treatment information, behavior, physical examination, standard laboratory measurements Facilitates implementation of new laboratory measurements  Collect and reposit specimens Facilitates nested studies Allows retrospective testing of specimens as new laboratory procedures become available Genetic data for predicting disease course/outcome and response to therapy

Incidence* of Seroconversion in the MACS by Center September 1995 Baltimore Chicago Pittsburgh Los Angeles Kingsley, Zhou,..., Muñoz - AJE 1991 (update) * Incidence = # of seroconverters per 1,000 person-semesters

Number of Participants with Specimens Available* in the National Repository Relative to the Time of Seroconversion** May 2011 * 2 or more tubes according to repository inventory as of 04/01/11 ** A total of 642 participants have a known seroconversion date Specimen Type Last Seronegative Visit First Seropositive Visit Plasma Serum Cells450443

MACS Cohort 6972 Seroconverter: 670 (16.4%)Seronegative: 3418 (83.6%) Seroprevalent: 2884 (41.4%)Seronegative: 4088 (58.6%) * HIV seronegative participants were administratively censored from the MACS in 1993 Active: 730 (67.7%) Active: 124 (77.5%) Active: 234 (75.2%) Active: 41 (75.9%) Active: 1182 (74.9%) Dead: 1451 (90.1%) Dead: 194 (15.2%) Dead: 260 (82.8%) Dead: 45 (12.6%) Dead: 132 (7.7%) Alive: 160 (9.9%) Alive: 1079 (84.8%) Alive: 54 (17.2%) Alive: 311 (87.4%) Alive: 1578 (92.3%) Created 4/11 Inactive 10/09 May 2011 AIDS: 1611 (55.9%) AIDS-Free: 1273 (44.1%) AIDS: 314 (46.9%) AIDS-Free: 356 (53.1%) Not Censored: 1710 (50.0%) Censored:* 1708 (50.0%)

Composition & Size of Cohort May 2011 Visit (Calendar year) # Participants (thousands) Seronegative Seroconverter Seroprevalent * 1710 have been administratively censored

Examples of Research Studies

Progression of HIV-1 Infection Prior to Potent Antiretroviral Therapy October median percent SCAIDS CD4 # 200DEATH AIDSDEATH 1199/ / /1620 OriginEvent Time in Years Muñoz, Xu. Stat Med 1996; Enger et al. JAMA 1996; Jacobson et al. AJE 1993 (update) Proportion

17 Mellors, Muñoz,…, Rinaldo. Ann Int Med 1997 Li, Buechner,…, Muñoz. Am Statistician 2003 Likelihood of Developing AIDS in Three, Six and Nine Years

Predictors of Short- and Long-Term Survival after Reaching <50 CD4+ T-cells/mm 3 (1) Marker Survival >18 months <6 monthsP T-cell reserve (N=26) (N=11) HLA-DR - CD38 - (resting) CD4 % 36 (8-49) 20 (4-43).02 HLA-DR - CD38 - (resting) CD8 % 22 (5-51) 13 (2-29).01

Predictors of Short- and Long-Term Survival after Reaching <50 CD4+ T-cells/mm 3 (2) Marker Survival >18 months <6 monthsP T-cell activation (N=26) (N=11) CD4 T-cell expression of CD38 (RFI)87 (28-466) 221 (59-487).002 CD8 T-cell expression of CD38 (RFI)190 (81-638) 411 ( ).001 HLA-DR + CD38 - CD8 %7 (0.7-18) 1.9 (0.4-8).002 Plasma HIV-1 copies/mL ( ) ( ).02 Interpretation: Activation is a more important determinant of survival at low CD4+ levels than viral load Giorgi et al., JID 1999; 179:

Detels/Imagawa Study, 1989 (1) Methods: Isolation studies (unique protocol) of 133 repeatedly exposed MSM Results: HIV isolations from 31; subsequently, four seroconverted months after positive isolation 27 isolation/PCR-positive MSM persistently antibody-negative 36+ months Interpretation: The 27 men cleared the virus Imagawa DT, et al. Human immunodeficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. N Engl J Med 1989; 320(22):

Resistant vs Susceptible MSM - Detels, 1994 Resistant MSM: 100 persistently HIV- negative highly exposed MSM Susceptible MSM: 77 low-risk seronegatives Results: Increased levels of neutrophils and CD8+ cells in resistant men Interpretation: CD8 cells may modulate outcome of HIV exposure Detels R, et al. Resistance to HIV-1 infection. J Acquir Immune Defic Syndr 1994; 7:

Genetic and Immunologic Studies of Resistant MSM - Detels, 1996 Immunologic Study 13 “resistant” MSM 27 seroconverters Results: Median percentage of CD25+/CD8+ activated cells higher in resistant men Genetic Study 23 resistant men 137 low-risk seroconverters Results: Significantly higher levels of TAP 1.4 and TAP 1.4/2.3 genes in resistant men Interpretation: Genetic factors (MHC transport?) are associated with resistance to infection Detels R, et al. Persistently seronegative men from whom HIV-1 has been isolated are genetically and immunologically distinct. Immunol Lett 1996; 51:29-33.

CCR5 Confers Protection Methods/Results: 111 resistant, 4.5% CCR5 homozygous 614 seropositive, 0% CCR5 homozygous Interpretation: 100% absence of CCR5 receptor on CD4 cells confers 100% protection Zimmerman PA, et al. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. Mol Med 1997; 3(1):23-36.

AIDS-Free Time by Calendar May 2000 Detels, Muñoz,..., Phair - JAMA 1998 (update) Years since Seroconversion Interpretation: HAART delays onset of AIDS

Effect of HLA-B Alleles on AIDS Progression (N=1,089) B*27B*57B*35Pxothers Time since seroconversion (year) Fraction AIDS 1987 free RH=0.4 9 P=0.001 RH=0.5 P=0.003 RH=1.92 p< Time since seroconversion (year) Fraction AIDS 1993 free RH=1.63 p< RH=0.43 p< RH=0.71 P=0.03 May 2006 Gao, Bashirova, …, Carrington. Nat Med 2005 Interpretation: HLA-B allele influences progression

A. Replication cohort (ALIVE, MACS, MHCS, SFCC, individuals genotyped by Steve O’Brien B. Combined analysis of replication and discovery cohorts (156 MACS individuals enriched with rapid progressors and long-term non-progressors Herbeck, Gottlieb, … Mullins. J Infect Dis 2010 May 2010 Kaplan-Meier Survival Curves for Genotypes of SNP rs , Representing a Haplotype Located 36kb Upstream of PROX1 and Chromosome 1, Showing Strong Associations with Differing Rates of Progression to Clinical AIDS

Time to AIDS Following HAART According to Selected Genotypings May 2009 Hendrickson, Jacobson,..., O’Brien - JAIDS 2008 Interpretation: CCR5-∆32 + SDF1-3’UTR delay onset of AIDS

Association between CD4+ T-cell Count (cells/µℓ) and Prevalence of Carotid Lesions among Participants in Men (MACS) and Women (WIHS) May 2009 Kaplan, Kingsley,..., Hodis - AIDS 2008 Prevalence ratio HIV-HIV+ HIV-HIV+ CD4> <200CD4> <200 N=325N=303N=147N=100N=50N=496N=487N=269N=288N=187 MenWomen Interpretation: Decreasing CD4+ level is associated with increasing CVD risk

Premature Aging of T cells Is Associated With HIV-1 Percentages of CD8+ T-cell subsets defined by expression patterns of CD28 and CD57 Interpretation: HIV-1 infection is associated with shift toward aged conformation of T- cells; i.e., HIV induces accelerated aging of T-lymphocytes Percentages of CD57+ cells within the CD4+ or CD8+ T cells Cao et al., JAIDS 50:142, 2009

An Evolving Scientific Agenda (partial) (1)  1985: HIV virology  1986: Neuropsychology  1987: Biostatistical methodology and therapeutics  1989: Cancer  1993: Health care utilization  1999: Metabolic complications

An Evolving Scientific Agenda (partial) (2)  2001: Hepatitis  2003: Cardiovascular disease  2005: Aging and sleep  2008: Renal complications and hearing and balance  2010: Genetic determinants of immune response and response to treatment  2010: Premature aging of immune function

Keys to Success 1. Commitment of the participants!!! 2. Dedication of the staff 3. Standardization and quality control of data collection, laboratory procedures, and record keeping 4. Decision to establish a repository of specimens 5. Reaching out to other investigators with essential expertise 6. Staying on the “cutting edge” 7. Consistent funding 8. Foresight and competence of original and subsequent investigators