supported by: niaid/nhlbi r24 ai067039, niaid r21 ai087360 viremia copy-years: a measure of...
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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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
Aims
Evaluate patient factors associated with VCY following modern cART initiation
Estimate the prognostic value of VCY following modern cART initiation
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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)
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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)
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
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
Supported by: NIAID/NHLBI R24 AI067039, NIAID R21 AI087360
Acknowledgements
• Co-authors• CNICS patients• CNICS site PIs & co-investigators• Stephen Van Rompaey• Donna Porter• CNICS site staff