DOSSIER

Web site: http://statepi.jhsph.edu/macs/macs.html Prepared by CAMACS Fax: 410-955-7587 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-35039, UO1-AI-35040, UO1-AI-35041, UO1-AI-35042, UM1-AI-35043, UL1-RR025005, (NCATS). December 2013

Multicenter AIDS Cohort Study (MACS) 7087 MSM enrolled in US • 4954 in 1984-85 • 668 in 1987-90 • 1350 in 2001-03 • 115 in 2010+

Study visits every 6 months • Standardized interviews, physical examination • Quality-controlled flow cytometry, HIV RNA quantification

Storage of biospecimens in local/national repositories

MACS Principal Investigators and Sites Roger Detels, Los Angeles

Lisa Jacobson, CAMACS

Joe Margolick, Baltimore

Otto Martinez-Maza, Los Angeles

Charles Rinaldo, Pittsburgh

Steven Wolinsky, Chicago December 2013

MACS Sites and Principal Investigators Sites: • • • •

Baltimore, MD (J. Margolick) Chicago, IL (S. Wolinsky) Los Angeles, CA (R. Detels, O. Martinez-Maza) Pittsburgh (C. Rinaldo)

Data Coordinating Center (CAMACS): • Baltimore, MD (L. Jacobson)

June 2011

MACS Working Groups  Aging ( J. Margolick)

 Liver (C. Thio)

 Behavioral (R. Stall)

 Malignancy/Pathology (E. Breen)

 Biomarkers (J. Bream)  Cardiovascular (W. Post)  Clinical (F. Palella)  Core Laboratory (B. Jamieson)  Data (A. Abraham)  Genetics (J. Martinson)

 Metabolic (T. Brown)  Neuropsychology (N. Sacktor)  Renal (M. Estrella / F. Palella)  Viral Immune Pathogenesis (J. Margolick) November 2013

Semiannual Visit  Questionnaire / ACASI • Medical History, Health Services, Behavior • Medications: Antiretrovirals, OIspecific, Adherence

 Labs • T-cells, HIV RNA, HBV & HCV serology • Lipids, liver and kidney function tests / anal cytology

 Demographics  Physical Examination / Lipodystrophy / Frailty  Psychosocial

• Quality of Life (SF36) • Depression (CESD) • Activities of Daily Living (IADL)

 Neuropsychological Screening

 Banked Specimens

• Plasma, Serum, Cells • B-cell lines • PBMC pellets May 2009

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

Data Collection Forms Drug Form 1 (anti-virals) Antiretroviral Medication Adherence Section 2* (demographics, depression (CESD)) Physical Exam / Lipodystrophy Exam Section 4 (medical history, health services, behavior*) Quality of Life* (SF36) Neuropsychological HIV Seroconversion Clinical Diagnostic Outcomes * Administered using Audio Computer Assisted Structured Interview (ACASI)

May 2009

Administrative Forms Data Set Transmission Study Investigator Registration for using MACS Specimens Restricted Use of MACS Specimens

May 2000

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 October 2013) Publications (published & in press)

1,306

Participants

7,087

Person-Years

93,710

Variables

12,357

Repository aliquots (plasma, serum, cells, urine)

1,743,937 HIV+

HIV-

Person-Visits

61,357

77,577

CD4 Measurements

56,144

62,252

HIV RNA Measurements

38,503

1,222 November 2013

MACS Cohort 7087*

Seroprevalent: 2963 (41.8%)

Created

Inactive 04/12

Seronegative: 4124 (58.2%) Seroconverter: 712 (17.3%)

AIDS: 1655 (55.9%) Alive: 161 (9.7%) Active: 126 (78.2%)

AIDS-Free: 1308 (44.1%)

Dead: Alive: 1494 1122 (90.3%) (85.8%) Active: 784 (69.9%)

Dead: 186 (14.2%)

5/13

AIDS: 333 (46.8%)

AIDS-Free: 379 (53.2%)

Alive: 57 (17.1%)

Dead: Alive: 276 335 (82.9%) (88.4%)

Active: 44 (77.2%)

Active: 247 (73.7%)

Dead: 44 (11.6%)

Seronegative: 3412 (82.7%) Not Censored: Censored: 1697 1715 (49.7%) (50.3%) Dead: 150 (8.7%)

Alive: 1565 (91.3%) Active: 1139 (72.88%)

* Includes 115 additional men (12 seronegatives, 103 seroprevalent, 24 with known seroconversion dates prior to entry) enrolled in the MACS per the 2010 recruitment protocol November 2013

Composition & Size of Cohort # Participants (thousands)

5 Seronegative Seroconverter

4

Seroprevalent

3

2

1

0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

Visit (Calendar year) * 1710 have been administratively censored

November 2013

Total # of CD4 and HIV RNA Measurements by Serostatus # per individual 0 1–4 5–8 9 – 12 13 – 16 17 – 20 21 – 24 25 – 28 29 – 32 33 – 36 37 – 40 41 – 44 45 – 48 49 – 52 53 – 54 55 – 56 57 - 58

Seronegative CD4 5 711 373 579 459 336 146 82 128 185 104 70 70 61 32 48 23

Seropositive (CD4 ; HIV RNA) 6; 804 ; 594 ; 476 ; 385 ; 402 ; 330 ; 72 ; 75 ; 75 ; 70 ; 64 ; 68 ; 81 ; 44 ; 62 ; 67 ;

326 1412 499 263 222 227 254 63 61 93 119 49 33 32 13 7 2 November 2013

Incidence* of Seroconversion in the MACS by Center Kingsley, Zhou, . . ., Muñoz - AJE 1991 (update) 60 Baltimore Chicago Pittsburgh Los Angeles

Incidence

50 40 30 20 10 0 84

86

88

90

92

94

Calendar Time (years) * Incidence = # of seroconverters per 1,000 person-semesters September 1995

Adjusted Time to HIV Seroconversion by  Methamphetamine (M) and Popper Use (P) 100

% HIV‐negative

98 M-/P-

96

M+/PM-/P+ M+/P+

94

92 Plankey,  Ostrow,… Jacobson.  JAIDS 2007;45:85‐92

90 0

5

10

Observation Time (years)

15

20 June 2008

Adjusted Time to HIV Seroconversion by Methamphetamine (M) Use and Number of Unprotected Receptive Anal Sex (URAS) Partners 100

98

M-/0 URAS

% HIV‐negative

M+/0 URAS M-/1 URAS

96

M+/1 URAS M-/2-4 URAS M+/2-4 URAS

94

M-/5+ URAS M+/5+ URAS

92 Plankey,  Ostrow,… Jacobson.  JAIDS 2007;45:85‐92

90 0

5

10

Observation Time (years)

15

20 June 2008

Adjusted Time to Recent HIV Seroconversion by Combinations of Sex-Drug Use Ostrow, Plankey, …, Stall. JAIDS 2009 100

% HIV-negative

N S P+E P E S+P

95

S+E 90

N = None S = Stimulant P = Poppers

S+P+E

E = EDD

85 0

1

2

3 4 5 6 Observation time (years)

7

8 May 2010

T-Cell Subset Changes and Homeostasis in AIDS-Free MACS Seroconverters Geometric Mean Absolute Cell Number (cells/µl)

Margolick, Muñoz, . . ., Ferbas – Nat Med 1995 2000

CD3 1500

CD8

1000

CD4

500

0 -24

-12

0

12

24

36

48

60

72

84

96

Months from Seroconversion October 1997

Kaplan-Meier Survival Curve for Inversion of the CD4/CD8 Ratio after the Estimated Time of HIV-1 Seroconversion Margolick, Gange, …, Lai. JAIDS 2006

Percent with CD4/CD8 > 1.0

1.0

0.8

0.6

0.4

0.2

0.0 0

12

24

36

48

60

72

84

96

108

Time from HIV seroconversion (Months)

120

132

144 May 2007

Histogram of 1222 CD4+ Regression Slopes Among HIV-1 Seropositive Men, 1984-1996 Muñoz, Kirby, . . ., Phair. JAIDS 1995 (update)

200 150 100 50

96 (7.9% above zero)

-762 -565 -527 -317 -314

0 -300

-200

-100

0

100

200

Slopes of CD4# (change per 6 months) June 1997

A Seropositive Triplet with Distinct Profiles

CD4 Nuumber

1200 1000 800 600 400 200 0 84

85

86

87

88

89

90

91

92

93

Calendar Time (years) Stable high CD4 AZT

Moderate CD4 decline AIDS

Rapid CD4 decline Death September 1995

Disease Progression Among Triplets of HIV- Infected Men with Distinct CD4 Trajectories Gange et al.

900

JAIDS 1997 (Update)

800

CD4 Count

700 600 500 400 300 200 100 0 1985

1987

1989

1991

1993

1995

1997

1999

Percent Reporting Potent Antiretroviral Therapy Use Without AIDS

0-10%

11-30%

31-60%

61-100%

With AIDS

0-10%

11-30%

31-60%

61-100% October 2000

Likelihood of Developing AIDS in HIV Infected Individuals with CD4 > 350 in the Non-HAART Era Phair, Mellors,…, Muñoz - AIDS 2002

>100 48

>90-100 31

>80-90 28

>70-80

HIV RNA (in thousands)

>50-60 >40-50 >30-40

>20-30 >10-20 >5-10 60-70

33

33%

Cumulative percentages of individuals in HIV-RNA categories

21%

Graphical Reference: Li, Buechner, …, Muñoz - Am Statistician 2003

November 2004

Likelihood of Developing AIDS in HIV Infected Individuals with 200 < CD4 < 350 in the Non-HAART Era Phair, Mellors,…, Muñoz - AIDS 2002 >100 77

>80-100 38

63

>60-80

HIV RNA (in thousands)

29

25

31

>40-60

100% 56

14

13

>20-40

68% 17

25

14

>10-20

61% 11

9

0

20,000

60,000

30K >55K

10K – 30K 3K – 10K 501 – 3K 750

Graphical Reference: Li, Buechner, …, Muñoz - Am Statistician 2003

November 2003

Likelihood of Developing AIDS in Nine Years Mellors, Muñoz, . . ., Rinaldo - Ann Int Med 1997

100% 80% 60% 40%

750

20% 0%

Count (cells/mm3)

>30K >55K

10K – 30K 3K – 10K 501 – 3K 750

Graphical Reference: Li, Buechner, …, Muñoz - Am Statistician 2003

November 2003

Effect of HLA-B Alleles on AIDS Progression (N=1,089) Gao, Bashirova, …, Carrington. Nat Med 2005

B*57

B*35Px

1.0

1.0

0.9

0.9

0.8 0.7 0.6

RH=0.43 p75th percentile + [1.5 x interquartile range]

50

40

30 P=0.004 20

LIPO+ HIV+ with Lipodystrophy

LIPOHIV+ without Lipodystrophy

HIVControls November 2013

Mean Trail-Making B Scores Around HIV-1 Seroconversion Vo, Cox, …, Miller - J Neurovirol 2013;19:24-31

November 2013

Mean Symbol-Digit Scores Around HIV-1 Seroconversion Vo, Cox, …, Miller - J Neurovirol 2013;19:24-31

November 2013

Mental and Physical Health Summary Score Change over the Course of HIV Disease Progression Liu, Ostrow, …, Jacobson. Qual Life Res 2006

Mean and 95% CI

60

Physical Health Summary Score Mental Health Summary Score

55

50

45

40 Pre_SC

No HAART

(npv=235)

(npv=242)

HAART