Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360 Viremia copy-years: A measure of...

Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360

Viremia copy-years:

A measure of cumulative HIV burden among patients initiating antiretroviral therapy

predicts long-term clinical outcomes

Michael Mugavero1, Sonia Napravnik2, Stephen Cole2, Joseph Eron2, Bryan Lau3, Heidi Crane4, James Willig1, Mari Kitahata4, Michael Saag1, and CFAR Network of

Integrated Clinical Systems (CNICS)

1 University of Alabama at Birmingham, 2University of North Carolina at Chapel Hill, 3Johns Hopkins University, and 4University of Washington


Background• Single plasma HIV viral load (VL) on

combination antiretroviral therapy (cART) predicts clinical outcomes (Egger M et al. Lancet 2002;360:119-29, Chene G et al. Lancet 2003;362:679-86, Lanoy E et al. AIDS 2009;23:2199-2208)

• But a single VL value cannot capture effects of intermittent viral replication over time

• Therefore, we developed viremia copy-years (VCY) to capture longitudinal cumulative VL burden


Viremia Copy-Years• Estimate of cumulative HIV burden over time

• Example: 10,000 copy-years1,000 c/mL per day for 10 years10,000 c/mL per day for 1 year

• VCY approximated as time-weighted sum using trapezoidal rule:

Cole SR et al. Am J Epidemiology 2010;171:198-205

iJ

i i i i i ij 1J t j t j 1 V j V j 1 / 2


Aims

Evaluate patient factors associated with VCY following modern cART initiation

Estimate the prognostic value of VCY following modern cART initiation


Methods• Cohort: CNICS

8-site US clinical cohort Kitahata et al., Int J Epi 2008. 37:948-955

• Eligibility CriteriaART-naïve initiating therapy 2000-08Initiated with modern cART

PI/r or NNRTI-based regimenAt least 12 months f/u from cART start

• Principal exposure: Viremia Copy-Years (VCY)


Methods• Relationships between patient factors and

VCY

Multivariable linear regression of log10 VCY with robust variances

• Relationship between log10 VCY and all-cause mortalityCox proportional hazards models


Results: Study Population

Characteristic (N=1906) N (%) or Median (IQR)Female 381 (20%)Black 724 (38%)Ritonavir-boosted PI 591 (31%)Pre-cART CD4 cell count, cells/mm3 181 (55, 282)Pre-cART log10 VL, copies/mL 4.9 (4.4, 5.4)Follow-up, years 3.5 (2.0, 5.4)VL measures contributed (n=24,105) 11 (6, 17)VCY, log10 copy-years/mL 2.76 (2.21, 3.89)VCY, copy-years/mL 575 (162, 7762)


Results: Relationship between patient factors and VCY from modern cART initiation

Patient Factors log10VCY a 95% CI P value

CD4 at cART-initiation (per 100 cell increase)

-0.08 -0.13, -0.03 <0.01

Women 0.41 0.19, 0.63 <0.01

Ritonavir-boosted PI b 0.34 0.17, 0.50 <0.01

a Multivariable linear regression model controlling for CD4 at cART initiation, sex, initial cART, duration of treatment and site.b Measured at cART-initiation, comparison group are patients initiating an NNRTI-based regimen, intention to treat approach * Higher pre-cART VL was associated with greater VCY in bivariable but not multivariable models


Results: Relationship between VCY and all-cause mortality from modern cART initiation

aMultivariable Cox proportional hazards model controlling for pre-cART VL, peak VL, time-updated VL, time-updated CD4, age, sex, initial cART (cART switches / discontinuations were not included), HIV acquisition mode, and site

Hazard Ratioa

95% CI P value

VCY, log10 copy-years/mL 2.16 1.15, 4.06 0.02

Pre-cART VL, log10 copies/mL 0.96 0.68, 1.36 0.82

Peak VL on cART, log10 copies/mL 0.79 0.46, 1.38 0.41

Time-updated VL, log10 copies/mL 1.18 0.91, 1.52 0.22

Time-updated CD4 (per 100 cell increase)

0.71 0.59, 0.85 <0.01


Conclusions• VCY, an estimate of cumulative HIV burden,

was associated with several patient characteristics following cART-initiation Independent of cross-sectional VL and CD4 cell count Among patients initiating modern cART regimens

• VCY had demonstrable prognostic value for all-cause mortality Independent of cross-sectional and time-updated VL and

CD4 measures, and other patient factors


Conclusions

• Future studies of VCY will include:Evaluating the effect of VCY on clinical outcomes among

specific groups of patients, including those with low-level or intermittent viremia

Estimating the relationship between VCY and AIDS- and non-AIDS events

Assessing relationships between VCY and markers of inflammation and immune activation


Acknowledgements

• Co-authors• CNICS patients• CNICS site PIs & co-investigators• Stephen Van Rompaey• Donna Porter• CNICS site staff

Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360 Viremia copy-years: A measure of...

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