denise evans, mhairi maskew, lynne mcnamara, patrick macphail, christopher mathews, ian sanne,...

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

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

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

• 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

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)

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)

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


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


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)

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

Virologic failure by risk score



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)


Risk category Virological failure

No Virologic Failure

≥ 4 (51.4%) 525 1364

< 4 (48.6%) 394 1392




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)




≥ 4 (51.4%) 525 1364

< 4 (48.6%) 394 1392




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)




≥ 4 (51.4%) 525 1364

< 4 (48.6%) 394 1392

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

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

% 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

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

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)

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)

Se/Sp of each score – Lynen et al., 2009

Se/Sp of each score – Meya et al., 2009

Se/Sp of each score – Robbins et al., 2010

denise evans, mhairi maskew, lynne mcnamara, patrick macphail, christopher mathews, ian sanne,...

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