CERVICAL CANCER DIAGNOSIS AND CD4+ COUNT TRAJECTORY IN HIV-INFECTED WOMEN IN NORTH AMERICAAlison Abraham, PhDDepartment of EpidemiologyJohns Hopkins Bloomberg School of Public Health

AG Abraham, S Gange, Y Jing, R Bosch, JT Brooks, R Dubrow, J Eron, K Gebo, MJ Gill, N Hessol, R Hogg, M Kitahata, M Klein, R Moore, S Rourke, M Silverberg, &G D’Souza, for the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)

IAS 2010Vienna, Austria

WEAB0104

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Cervical cancer and HIV Human papillomavirus (HPV) is a

common sexually transmitted infection causally linked to cervical cancer

Most cervical HPV infections clear but in some women they persist and cause cervical cancer

Chronic immunosuppression in HIV-infection may promote HPV persistence and increase the risk of cervical cancer

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This study explored whether lower CD4 counts over time could result in higher risk of progression to cervical cancer

Does chronic immunosuppression contribute to cervical cancer risk?

NA-ACCORD is a collaboration of over 20 existing HIV research studies and>110,000 subjects

Part of the NIH/NIAIDIeDEA Network

North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD)

Gange, Kitahata, Saag, …, & Moore. Int J Epi 2007

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Study Design &Population HIV-infected women from 13 North American

cohorts contributing to NA-ACCORD Clinical and interval cohorts

Nested case-control study Cases: Invasive cervical cancer

Clinically confirmed or cancer registry-linked cervical cancer diagnoses

Occurring after ART initiation Controls: Women without ICC diagnosis over

follow-up

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Methods Controls were matched at ART initiation on:

CD4+ cell count, Age, Cohort, Calendar Year, Follow-up time

All controls which met the matching criteria were included to maximize available CD4 trajectory information

We modeled trends in average CD4 counts using: Piecewise-linear mixed effects models Spline terms added at ART initiation and one year

following initiation Interaction terms to describe differences between cases

and controls

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Characteristics at ART initiation

Invasive Cervical Cancer Cases (N=56)

Controls(N=503)

Median [IQR]Age 40 [33-45] 40 [36-46]Median [IQR] CD4 242 [87-353] 230 [83-328]Median [IQR] HIV RNA

4,869 [658-54,277] 2,360 [<300-54,027]

African American 55% 57%Inj. drug use Hx 29% 37%NRTI use prior to ART

23% 26%

Type of ART: PI-based 45% 49% NNRTI-based 39% 36%No statistically significant differences were noted IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

Areas under the CD4 Curve for Cases approximately

80% of Controls

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Months from ART Initiation

CD4+

Cou

nt (c

ells/

μl)

ControlsCases

Mean CD4 and 95% CI

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Estimated CD4 trajectories

Parameter Control (95% CI)

Control - Case (95% CI)

Mean CD4 at ART (cells/μl) 250 (201, 299) 10.9 (-40.5, 62.3)

CD4 Slope (cells/μl per month)

-4 years to 0 [ART Initiation]

-1.4 (-2.2, -0.5) -3.6 (-6.3, -0.9)*

0 to 1-year post-ART 9.4 (8.2, 10.5) 8.1 (3.7, 12.4)*

1-year post-ART to ICC 2.3 (1.5, 3.1) 1.6 (2.5, 5.8)*p<0.05 for test of equality of case and control parameters IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Modeling CD4 trajectory

Time point Difference in mean CD4 count

Controls - Cases

4 years pre-ART 163 (29, 296)*

1 year pre-ART 32 (-25, 90)

1 year post-ART 43 (-17, 102)

2 years post-ART 96 (5, 188)*

4 years post-ART 164 (46, 282)**p<0.05 IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

IAS 2010 - Vienna, Austria – Oral Abstract WEAB010411

Viral Load Changes Appeared Similar

No significant differencesin the geometric mean viral

loads at any time point tested

Months from ART Initiation

Vira

l Loa

d (lo

g ba

se 1

0), c

opie

s/m

l

ControlsCases

Geometric mean VL and 95% CI

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

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Average CD4 counts were consistently lower over time for women who developed ICC than for similar women who remained free of ICC over follow-up

These differences in CD4 trajectory between cases and controls suggest a role of long-term immunosuppression

Less robust rebound in CD4 following ART was not explained by differences in viral load (adherence) or prior NRTI exposure (resistance)

Conclusions

13 Large study of cervical cancer among HIV-infected

women The size of NA-ACCORD allowed for both large numbers of

cases to be found and the ascertainment of appropriate controls for the current study

Rigorous quality assurance protocol to assemble data from different cohorts into single dataset Validated data on CD4 history for cases and controls for

evaluating trajectory differences Limited covariate information

No information on Pap screening (potentially heterogeneous between cohorts) or hysterectomy

Strengths and Limitations

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104

14NA-ACCORD cohorts: VACS: Robert Dubrow, Yale University ALLRT: Ronald Bosch, Harvard; Constance Benson, UCSD; Ann Collier, UW Seattle Montreal: Marina Klein, Montreal Chest Institute HIV Clinic, McGill University HIVRN: Kelly Gebo, Johns Hopkins School of Medicine HOPS: John T. Brooks, CDC JHHCC: Richard Moore, Johns Hopkins School of Medicine KPNC: Michael Silverberg & Michael Horberg, Kaiser Permanente Northern California SAC: M. John Gill, University of Calgary, Southern Alberta UCHCC: Joseph Eron & Sonia Napravnik, University of North Carolina, Chapel-Hill UW: Mari Kitahata, University of Washington at Seattle HOMER:RobertHogg, BC Centre for Excellence and HIV/AIDS; Simon Fraser University OHTN Sean Rourke & Anita Rachlis, University of Toronto, Canada WIHS: Nancy Hessol, UCSF, Women’s Interagency HIV StudyTHANKS TO: National Institute of Allergy & Infectious Diseases, with supplemental

funding from the National Cancer Institute

Acknowledgements

IAS 2010 - Vienna, Austria – Oral Abstract WEAB0104