The Positive Predictive Value of World Health Organization (WHO) Immunologic Criteria for Treatment Failure in a Public Health Antiretroviral Delivery Network in Africa

E.H. Geng1, K. Wools-Kaloustian2, A. Siika3, B. Musick2, D. Lameck3, R. Kantor4, J. Hogan5, S.G., Deeks1, C. Yiannoutsos2, J.N. Martin1, all of the East Africa IeDEA Consortium1 University of California at San Francisco, Medicine, San Francisco, 2 Indiana University School of Medicine, Medicine, Indianapolis, 3 Moi University School of Medicine, Medicine, Eldoret, Kenya, 4 Brown University, Medicine, Providence, United States,5 Brown University, Biostatistics, Providence, USA

Conclusions

• In the absence of routine HIV RNA determination, this study supports continued use of WHO immunologic failure criteria to guide switch decisions: even though the PPV’s are suboptimal, the risk of virologic failure in individuals with immunologic failure is high enough to warrant switch for an individual patient.

• The differences between each criteria are not sufficiently discriminatory to recommend different clinical responses to each criteria.

• More than half of these switches, however, using these criteria are unnecessary and increase the cost of global ART delivery.

• In settings where HIV RNA determination is available only when clinical indicated, patients with immunologic failure should be considered candidates for HIV RNA testing.

• Point-of-care qualitative HIV RNA testing is an urgent priority in resource-limited settings

Background Results

Methods

e-poster abstract number [A-155-0153-02747]

• 1950 patients followed for a maximum of 4.6 years had an HIV RNA determination. 927 (48%) experienced an episode of immunologic failure.

• In 609 (61%) the HIV RNA determination was within the ensuing 12 months and before regimen switch.

• Millions of HIV-infected patients in Africa are starting life-long regimens of antiretroviral therapy (ART) without the benefit of routine HIV RNA monitoring.

• The World Health Organization (WHO) has proposed immunologic criteria for switch to second line therapy.

• The positive predictive value (PPV) of these criteria for detectable HIV RNA levels in routine clinical practice is not well characterized.

Patients

• We examined patients starting ART from Jan. 1st, 2004 & Sept. 1st, 2008 in the Academic Model Providing Access to Healthcare network in Kenya who had a clinically indicated HIV RNA determination.

Implications

Measurements

• Clinical and demographic characteristics were obtained from the OpenMRS electronic medical records systems at each site.

• We considered immunologic failure (IF) Type 1 to be a CD4 count of < 100/mm3 after six months of therapy, Type 2 to be a 50% decline from on-treatment peak and Type 3 to be a fall below the last pre-therapy value.

• Plasma HIV RNA determinations within 12 months of an immunologic failure event were considered in PPV calculations.

Analyses • We examined the proportion of patients with an immunologic failure

event who had detectable HIV RNA at 1000 and 10,000 c/ml to calculate the PPV of immunologic failure criteria for virologic failure.

• We fitted a multivariable logistic regression model to identify other factors associated with detectable viremia.

• PPV’s of immunologic failure criteria for virologic failure were suboptimal: most patients with immunologic failure did not have virologic failure.

• Among the criteria examined, a CD4 value 50% below on-treatment peak yielded the highest PPV for viremia while a failure to rise more than 100 cells after six months of therapy led to the lowest. Combined immunologic failure criteria did not change predictive values substantively.

• Among patients with immunologic failure, clinical factors such as time on treatment and age further risk stratify for the occurrence of virologic failure.

• Over a maximum of 4.6 years, the median time of immunologic failure was the shortest for Type 1 alone (9.8 months, IQR 7.2-11.5) and longest for Type 2 alone (19.7, 13.8-26.6).

Results

• At the time of first immunologic failure, Type 3 was the most common form followed by Type 2 and Type 1. Overlap was greatest between Types 2 and 3.

• CD4 determinations were made a median of 184 days apart (IQR, 167-204). The intervals were similar over time.

• The PPV of immunologic failure Types 1, 2 and 3 for HIV RNA levels > 1000 c/ml were 28.9, 48.7 and 37.0%. At a cut off of 10,000 c/ml the values were 18.5, 32.8 and 22.3% respectively.

• Combined occurrence of immunologic failure types at the time of first failure yielded PPV’s of 33.3, 47.6 & 37.6% for HIV RNA level > 1000 c/ml and 22.2, 30.2 and 23.3 for 10,000 c/ml.

• In a model using an outcome of HIV RNA > 10,000 c/ml, each six months on ART was associated with risk of viremia (OR 1.52, 95% CI 1.29-1.78) as was age (OR 0.76, 95% CI 0.60-0.95).

Type1 Type2 Type3 T.1&2 T.1&3 T.2&3 Any

No with IF event 284 477 522 19 48 188 927

No w/ viral load w/i 1 year

173 314 346 13 27 126 609

No VL> 1000c/ml 50 153 128 4 9 60 229

PPV VL>1000 c/ml 28.9 48.7 37.0 30.8 33.3 47.6 37.6

No VL>10,000c/ml 32 103 77 3 6 38 143

PPV VL >10,000 c/ml 18.5 32.8 22.3 23.1 22.2 30.2 23.3

Positive Predictive Values of Immunologic Failure Criteria (n=927)

29

49

37 37

19

33

22 23

0

10

20

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40

50

60

Rise < 100 cells Fall > 50% frompeak

Fall to lessthan pre-therapy

AnyPo

siti

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alu

e (%

)

1000 c/ml 10000 c/ml

• In a multivariable model among patients who had an immunologic failure event, each six months on ART (OR 1.19, 95% CI 1.15-1.27) and each 10 years in age (OR 0.87, 95% CI 0.75-0.99) were associated with risk of viremia at 1000 copies/ml.

First Occurrence of Immunologic Failure, n= 609

IF1=185

IF2=331 IF1&2=16

IF3=379

IF1&2&3=10

IF2&3=153

IF1&3=35

01

02

03

04

0T

ime

sin

ce A

RT

Initi

atio

n (m

onth

s)

excludes outside values

Time on ART at Immunologic Failure Event, N=609

Type 1 Type 2Type 3 Type 1&2

Type 1&3 Type 2&3

50

100

150

200

250

300

Tim

e s

ince

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s C

D4

dete

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ays

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1 2 3 4 5 6 7 8On Therapy CD4 Determination Number

excludes outside values

Time between CD4 Determinations