denise evans, mhairi maskew, lynne mcnamara, patrick macphail, christopher mathews, ian sanne,...
TRANSCRIPT
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Denise Evans, Mhairi Maskew, Lynne McNamara, Patrick MacPhail,
Christopher Mathews, Ian Sanne, Matthew Fox
CD4 criteria improves the sensitivity of a clinical algorithm developed to identify viral failure in HIV-positive patients on
first-line antiretroviral therapy
This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through South Africa Mission of the US Agency for International Development (USAID) under the terms of grant number 674-A-00-08-00007-00
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Background• Routine viral load monitoring is neither affordable nor available
in most resource-limited settings – Previous attempts to identify low-cost surrogate markers of virologic failure have
shown conflicting results (Lynen et al., 2009; Robbins et al., 2010; Meya et al., Johannessen et al., 2008; Lawn et al., 2006)
– Need to develop simpler, cheaper monitoring strategies that can be administered by
minimally trained clinic personnel
• Used data from a large South African clinic to try to develop an algorithm using accessible, inexpensive, routinely collected markers to identify virological failure
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Human Research Ethics Committee of the University of the Witwatersrand (HREC M060623/M110140/M10418)
Methods• Study site and subjects
– Themba Lethu Clinic, Johannesburg, South Africa, >20,000 patients on ART– Included non-pregnant, HIV+ ART naïve adults (≥18)– Initiated on public sector first-line regimen, April 2004 – February 2010– Limited to those with ≥2 viral load and >6 months on ART
• Study data– Included inexpensive, routinely collected baseline and follow-up markers
• e.g. BMI, blood pressure, WHO staging, hemoglobin, albumin, mean cell volume, new conditions, CD4 count etc.
• WHO failure criteria: WHO stage III/IV, CD4 < baseline or < 100 cells/mm3
– Matched virologic failures to comparison group (1:3) on person-time
• Outcomes– Virological failure: 2 HIV-RNA ≥400 copies/ml after suppression
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• Cox PH model to identify important predictors of viral failure to create risk score– Univariate p < 0.1 included (age and gender)– Risk score calculated by assigning rounded aHR for
each predictor*• E.g. if low BMI has aHR 1.75 = +2
– For each subject, total score is sum of risk scores
– Low risk (0-4), Medium/High risk (≥ 4)**
• Assessed diagnostic accuracy of risk groups with virologic failure as gold standard – Se, Sp, PPV, NPV– Model with and without CD4 criteria
Themba Lethu Clinic, Johannesburg
Statistical analysis
*Spiegelhalter and Knill-Jones method; Berkley et al., 2003; Lynen et al., 2009 **Robbins et al., 2010
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Baseline characteristics Virologic failure (n = 919)
No virologic failure (n = 2756)
Male 342 (39.7%) 1095 (39.0%)Age [Median (IQR)] 34.7 (30.2 – 41.4) 36.2 (31.1 – 42.8)Body mass index (kg/m2) 21.4 (18.9 – 24.6) 21.3 (18.8 – 24.3)
<18.5 kg/m2 177/856 (20.7%) 544/2515 (21.6%)CD4 cell count (cells/mm3) 65 (23 – 130) 89 (34 – 154)CD4 <100 cells/mm3 548/831 (65.9%) 1374/2530 (54.3%)Hemoglobin (g/dl) 11.4 (10.0 – 12.9) 11.5 (10.0 – 13.0)Viral load >100 000 copies/ml 98/194 (50.5%) 280/687 (40.8%)WHO stage III/IV 385/830 (46.4%) 1030/2493(41.3%)First regimen
d4T-3TC-EFV 778 (84.7%) 2408 (87.4%)
d4T-3TC -NVP 94 (10.2%) 185 (6.7%) Other 47 (5.1%) 163 (5.9%)Tuberculosis at ART initiation 171 (18.6%) 438 (15.9%)Time on ART (months) [Median (IQR)] 26.4 (15.4 – 42.2) 26.2 (15.4 – 42.1)
Matched Results (n=3675)
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Baseline characteristics Virologic failure (n = 919)
No virologic failure (n = 2756)
Male 342 (39.7%) 1095 (39.0%)Age [Median (IQR)] 34.7 (30.2 – 41.4) 36.2 (31.1 – 42.8)Body mass index (kg/m2) 21.4 (18.9 – 24.6) 21.3 (18.8 – 24.3)
<18.5 kg/m2 177/856 (20.7%) 544/2515 (21.6%)CD4 cell count (cells/mm3) 65 (23 – 130) 89 (34 – 154)CD4 <100 cells/mm3 548/831 (65.9%) 1374/2530 (54.3%)Hemoglobin (g/dl) 11.4 (10.0 – 12.9) 11.5 (10.0 – 13.0)Viral load >100 000 copies/ml 98/194 (50.5%) 280/687 (40.8%)WHO stage III/IV 385/830 (46.4%) 1030/2493(41.3%)First regimen
d4T-3TC-EFV 778 (84.7%) 2408 (87.4%)
d4T-3TC -NVP 94 (10.2%) 185 (6.7%) Other 47 (5.1%) 163 (5.9%)Tuberculosis at ART initiation 171 (18.6%) 438 (15.9%)Time on ART (months) [Median (IQR)] 26.4 (15.4 – 42.2) 26.2 (15.4 – 42.1)
Matched Results (n=3675)
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Risk factor Crude HR 95% CI Adjusted HR 95% CI Score
Gender - Male 0.97 (0.85 – 1.11) 0.95 (0.77 – 1.15) + 0
Age > 40 years 1.16 (1.03 – 1.33) 1.30 (1.06 – 1.60) + 1
Albumin <25 g/l 1.20 (1.01 – 1.42) 1.15 (0.95 – 1.45) + 1
CD4 cell count <100 cells/mm3 1.35 (1.17 – 1.56) 1.20 (1.09 – 1.48) + 1
WHO stage III/IV 1.16 (1.01 – 1.33) 1.26 (1.02 – 1.57) + 1
Base
line
Multivariate risks scores (HRs)
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Risk factor Crude HR 95% CI Adjusted HR 95% CI Score
Gender - Male 0.97 (0.85 – 1.11) 0.95 (0.77 – 1.15) + 0
Age > 40 years 1.16 (1.03 – 1.33) 1.30 (1.06 – 1.60) + 1
Albumin <25 g/l 1.20 (1.01 – 1.42) 1.15 (0.95 – 1.45) + 1
CD4 cell count <100 cells/mm3 1.35 (1.17 – 1.56) 1.20 (1.09 – 1.48) + 1
WHO stage III/IV 1.16 (1.01 – 1.33) 1.26 (1.02 – 1.57) + 1
New condition/diagnosis 1.34 (1.16 – 1.55) 1.14 (0.97 – 2.07) + 1
Worsening of WHO stage 1.24 (1.04 – 1.48) 1.17 (0.98 – 1.41) + 1
Mean cell volume (MCV) <100 fl 1.29 (1.12 – 1.49) 1.23 (1.02 – 1.49) + 1
CD4 cell count <200 cells/mm3 1.37 (1.19 – 1.59) 1.28 (1.02 – 1.60) + 1
Hemoglobin drop >20% 1.60 (1.05 – 2.45) 1.38 (0.97 – 2.77) + 1
WHO stage III/IV 1.52 (1.08 – 2.13) 1.58 (1.03 – 2.46) + 2
Base
line
6-12
mon
ths
befo
re fa
ilure
Multivariate risks scores (HRs)
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Virologic failure by risk scoreRisk category Virological
failure No Virologic
Failure
≥ 4 (51.4%) 525 1364
< 4 (48.6%) 394 1392
Criteria Se Sp PPV NPV
Clinical & immunological WHO criteria* √
25.2 (22.8 – 27.8)
70.6(69.8 – 71.5)
22.3 (20.1 – 24.6)
73.9 (73.1 – 74.8)
*Lynen et al., 2009; Meya et al., 2009 √ WHO stage III/IV, CD4 < baseline or CD4 < 100cells/mm3
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Virologic failure by risk score
Criteria Se Sp PPV NPV
Clinical & immunological WHO criteria* √
25.2 (22.8 – 27.8)
70.6(69.8 – 71.5)
22.3 (20.1 – 24.6)
73.9 (73.1 – 74.8)
WHO stage III/IV* 20.9 (18.4 – 23.6)
73.7 (72.8 – 74.6)
21.7 (19.1 – 24.4)
72.8 (72.0 – 73.7)
*Lynen et al., 2009; Meya et al., 2009 √ WHO stage III/IV, CD4 < baseline or CD4 < 100cells/mm3
Risk category Virological failure
No Virologic Failure
≥ 4 (51.4%) 525 1364
< 4 (48.6%) 394 1392
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Virologic failure by risk score
Criteria Se Sp PPV NPV
Clinical & immunological WHO criteria* √
25.2 (22.8 – 27.8)
70.6(69.8 – 71.5)
22.3 (20.1 – 24.6)
73.9 (73.1 – 74.8)
WHO stage III/IV* 20.9 (18.4 – 23.6)
73.7 (72.8 – 74.6)
21.7 (19.1 – 24.4)
72.8 (72.0 – 73.7)
Score without CD4 criteria (≥4 v. <4)
38.0 (34.8 – 41.2)
65.4 (63.6 – 67.2)
26.8 (24.4 – 29.3)
76.0(74.2 – 77.7)
*Lynen et al., 2009; Meya et al., 2009 √ WHO stage III/IV, CD4 < baseline or CD4 < 100cells/mm3
Risk category Virological failure
No Virologic Failure
≥ 4 (51.4%) 525 1364
< 4 (48.6%) 394 1392
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Virologic failure by risk score
Criteria Se Sp PPV NPV
Clinical & immunological WHO criteria* √
25.2 (22.8 – 27.8)
70.6(69.8 – 71.5)
22.3 (20.1 – 24.6)
73.9 (73.1 – 74.8)
WHO stage III/IV* 20.9 (18.4 – 23.6)
73.7 (72.8 – 74.6)
21.7 (19.1 – 24.4)
72.8 (72.0 – 73.7)
Score without CD4 criteria (≥4 v. <4)
38.0 (34.8 – 41.2)
65.4 (63.6 – 67.2)
26.8 (24.4 – 29.3)
76.0(74.2 – 77.7)
Score with CD4 criteria (≥4 v. <4)
57.1 (53.9 – 60.4)
50.5(48.6 – 52.4)
27.8(25.8 – 29.9)
77.9(75.9– 79.8)
*Lynen et al., 2009; Meya et al., 2009 √ WHO stage III/IV, CD4 < baseline or CD4 < 100cells/mm3
Risk category Virological failure
No Virologic Failure
≥ 4 (51.4%) 525 1364
< 4 (48.6%) 394 1392
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Conclusions
• Average sensitivity and poor specificity of virologic failure • Similar to previous scoring systems
– Total score without CD4 criteria improved Se over WHO criteria or WHO stage III/IV
– CD4 criteria further improves Sensitivity• Limitations
– Missing values (20-25%)– Data from a single site (validate)– Could only evaluate what actually happened, not whether method
could predict future events• Looking at further refinements of the model• Could be useful to screen for risk of virologic failure
– Absence of routine viral load testing, targeted laboratory testing
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AcknowledgementsNIH and USAIDHE2RO/CHRU – WITS Health Consortium Hazel Molefe Daphne Radebe Bontle Mahlatsi
Desiree LouwKeagile Komane
Frank Phakathi
University of California – San Diego
Right to Care
Patients and staff at Themba Lethu Clinic – Helen Joseph Hospital
This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through South Africa Mission of the US Agency for International Development (USAID) under the terms of grant number 674-A-00-08-00007-00
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% n=3675
Se Sp PPV NPV OR
Male gender 100% 37.2 (34.5-40.0) 60.3 (59.4-61.2) 23.8 (22.0-25.6) 74.2 (73.1-75.4) 0.90 (0.77-1.05)
Age > 40 years 100% 70.2 (67.5-72.8) 34.8 (33.9-35.7) 26.4 (25.4-27.4) 77.8 (75.8-79.7) 1.26 (1.07-1.48)
CD4 cell count <100 cells/mm3 91.5% 65.9 (63.0-68.8) 45.7 (44.7-46.6) 28.5 (27.2-29.7) 80.3 (78.6-82.0) 1.63 (1.38-1.93)
WHO stage III/IV 90.4% 46.4 (43.4-49.4) 58.7 (57.7-59.7) 27.2 (25.5-29.0) 76.7 (75.4-78.0) 1.23 (1.05-1.44)
Albumin <25 g/l 87.4% 21.7 (19.2-24.3) 80.6 (79.8-81.4) 26.6 (23.6-29.8) 76.0 (75.2-76.8) 1.15 (0.94-1.41)
Hemoglobin drop >20% 77.2% 2.7 (1.8-3.6) 98.2 (97.9-98.6) 37.9 (25.9-51.5) 71.2 (70.9-71.5) 1.51 (0.85-2.66)
BMI drop >10% 83.4% 2.1 (1.3-3.1) 98.3 (98.0-98.7) 30.9 (19.6-44.8) 73.9 (73.7-74.2) 1.27 (0.68-2.33)
Mean cell volume (MCV) <100 fl 72.4% 50.2 (47.2-53.2) 52.3 (51.1-53.6) 30.2 (28.4-32.0) 71.9 (70.2-73.6) 1.11 (0.93-1.31
CD4 cell count <200 cells/mm3 76.4% 34.7 (31.9-37.6) 58.2 (57.1-59.4) 25.6 (23.5-27.7) 68.3 (67.0-69.7) 1.35 (1.14-1.61)
Missed medical visit >7days 90.4% 8.3 (6.8-10.0) 93.5 (93.0-94.1) 31.0 (25.4-37.2) 74.4 (74.0-74.9) 1.31 (0.97-1.76)
Worsening of WHO stage 77.3% 4.7 (3.5-6.2) 95.4 (94.9-95.9) 26.5 (19.5-34.8) 74.1 (73.7-74.5) 1.03 (0.68-1.56)
New condition/diagnosis 100% 26.6 (24.1-29.1) 71.4 (70.6-72.3) 23.7 (21.5-26.0) 74.5 (73.6-75.4) 0.90 (0.76-1.07)
Sub-optimal adherence 54.2% 11.8 (9.4-14.5) 88.3 (87.5-89.2) 25.2 (20.1-30.9) 75.0 (74.3-75.7) 1.01 (0.73-1.40)
Regimen change/substitution 100% 24.0 (21.7-26.5) 82.1 (81.3-82.9) 30.9 (27.9-34.0) 76.4 (75.7-77.2) 1.45 (1.21-1.74)
Missed ARV visit current/previous 85.3% 6.9 (5.4-8.5) 93.3 (92.8-93.8) 26.4 (20.9-32.7) 74.0 (73.6-74.4) 1.02 (0.73-1.42)
WHO stage III/IV 81.2% 20.9 (18.4-23.6) 73.7 (72.8-74.6) 21.7 (19.1-24.4) 72.8 (72.0-73.7) 0.74 (0.61-0.91)
Individual Se/Sp of variables
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Reference Se Sp PPV NPV
Lynen et al., JAIDS 2009 (score 4)12.6
(6.8 – 22.3)99.7
(99.3 – 99.9)68.8
(41.7 – 87.1)95.7
(94.4 – 96.8)
Meya et al., JIAS 2009
(CD4, VL, missed visits)
67.0(63.0 – 71.0)
82.0 (79.0 – 85.0)
24.0 (20.0 – 28.0)
97.0 (96.0 – 99.0)
Robbins et al., CID 2010 Derivation
Validation
30.6%
28.6%
94.6%
92.3%
Mee et al., AIDS 2008 CD4 criteria
Clinical criteria
21.2%
15.2%
95.8%
88.1%
36.8%
12.8%
Badhi et al., BMC 2008 CD4 criteria 53.0% 63.6% 10.9%
Se/Sp of algorithms in literature
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Se/Sp of each score
Criteria (Med/High v. Low) Se Sp PPV NPV
≥ 1 vs. < 1 98.8(97.9 – 99.4)
2.6(2.0 – 3.3)
25.3(23.9 – 26.7)
86.7(77.5 – 93.2)
≥ 2 vs. < 2 91.1 (89.0 – 92.8)
14.8 (13.5 – 16.2)
26.3 (24.8 – 27.8)
83.3(79.7 – 86.5)
≥ 3 vs. < 3 75.7 (72.8 – 78.5)
32.9 (31.1 – 34.7)
27.3 (25.6 – 29.1)
80.2 (77.8 – 82.5)
≥ 4 vs. < 4 57.1 (53.9 – 60.4)
50.5(48.6 – 52.4)
27.8(25.8 – 29.9)
77.9(75.9– 79.8)
≥ 5 vs. < 5 37.3 (34.2 – 40.5)
66.3(64.5 – 68.1)
27.0 (24.5 – 29.5)
76.0(73.1 – 74.8)
≥ 6 vs. < 6 23.2 (20.5 – 26.0)
78.4 (76.8 – 79.9)
26.3 (23.3 – 29.5)
75.4 (73.7 – 76.9)
≥ 7 vs. < 7 12.9 (10.8 – 15.3)
87.8(86.5 – 89.0)
26.1 (22.1 – 30.4)
75.1 (73.6 – 76.6)
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Se/Sp of each score excluding variables with < 80% of the data
Criteria (Med/High v. Low) Se Sp PPV NPV
≥ 1 vs. < 1 97.3 (96.0 – 98.2)
4.5 (3.7 – 5.3)
25.3 (23.9 – 26.8)
83.1 (76.1 – 88.8)
≥ 2 vs. < 2 84.3(81.8 – 86.6)
21.9 (20.4 – 23.5)
26.5 (24.9 – 28.1)
80.7 (77.7 – 83.5)
≥ 3 vs. < 3 64.1 (60.9 – 67.2)
44.3 (42.5 – 46.2)
27.7 (25.8 – 29.7)
78.7 (76.6 – 80.7)
≥ 4 vs. < 4 41.3 (38.1 – 44.6)
62.0 (60.1 – 63.8)
26.6(24.3 – 29.0)
76.0(74.2 – 77.8)
≥ 5 vs. < 5 22.3(19.7 – 25.1)
77.0 (75.4 – 78.6)
24.5 (21.6 – 27.5)
74.8(73.2 – 76.4)
≥ 6 vs. < 6 11.0 (9.0 – 13.2)
87.9 (86.6 – 89.1)
23.2(19.3 – 27.5)
74.8 (73.2 – 76.2)
≥ 7 vs. < 7 4.5(3.2 – 6.0)
94.7 (93.8 – 95.5)
21.9 (16.2 – 28.5)
74.8(73.4 – 76.3)
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Se/Sp of each score – Lynen et al., 2009
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Se/Sp of each score – Meya et al., 2009
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Se/Sp of each score – Robbins et al., 2010