Evaluation of the WHO immunologic criteria for treatment failure among adults on first-line HAART in south India Snigdha Vallabhaneni 1, Sara Chandy 2,

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Evaluation of the WHO immunologic criteria for treatment failure among adults on first-line HAART in south India Snigdha Vallabhaneni 1, Sara Chandy 2, Elsa Heylen 1, Maria Ekstrand 1,2 (1)Center for AIDS Prevention Studies, University of California, San Francisco, USA (2) St John’s National Academy of Health Sciences, Bangalore, India

Objectives Evaluate the test performance characteristics of WHO criteria for immunologic failure (IF), compared against virologic failure (VF) in the Indian setting. Assess the genotypic consequences of staying on a failing regimen. Methods Longitudinal cohort study ( ) in Bangalore, India 522 HIV+ participants on HAART for at least 6 months. CD4, VL, and genotype every 6 months for 24 months. IF = fall of CD4 to pre-tx baseline, ≥50% fall from peak, persistently <100 cells/mm 3. VF = 2 VL ≥ 1000 copies/ml or 1VL ≥ 10,000 copies/ml.

VF+VF-Total IF IF Total Test Characteristics of WHO- IF criteria to detect VF Sensitivity: 22.8% (95% CI: ) Specificity: 93.8% (95% CI: ) Mutation (Mut) Mut at time VF detectedMut during study Mut at end of study VF at enrollment (N=29) VF during study (N=15)(N=44) NRTI MUTATIONS M18425 (86%)8 (53%)+740 (91%) Any TAMS16 (55%) (66%) 1 TAM608 2 TAMs6011 ≥ 3 TAMS /Q151M2 (7%)0+57 (16%) K65R/70E4 (14%)0+04 (9%) TDF resistance6 (21%)0+915 (35%) NNRTI MUTATIONS K103N7 (24%)2 (13%)+312 (27%) Y181C15 (52%)2 (13%)+219 (43.%) G190A7 (24%)5 (33%)+618 (41%) K101E6 (21%)1 (7%)+613 (30%) ETR score>2.518 (62%)2 (13%)+828 (65%) Genotypic consequence of staying on a failing regimen (N=44) Results PPV: 31.0% 95%CI:

VF+VF-Total IF IF Total Test Characteristics of WHO- IF criteria to detect VF Sensitivity: 22.8% (95% CI: ) Specificity: 93.8% (95% CI: ) Mutation (Mut) Mut at time VF detectedMut during study Mut at end of study VF at enrollment (N=29) VF during study (N=15)(N=44) NRTI MUTATIONS M18425 (86%)8 (53%)+740 (91%) Any TAMS16 (55%) (66%) 1 TAM608 2 TAMs6011 ≥ 3 TAMS /Q151M2 (7%)0+57 (16%) K65R/70E4 (14%)0+04 (9%) TDF resistance6 (21%)0+915 (35%) NNRTI MUTATIONS K103N7 (24%)2 (13%)+312 (27%) Y181C15 (52%)2 (13%)+219 (43.%) G190A7 (24%)5 (33%)+618 (41%) K101E6 (21%)1 (7%)+613 (30%) ETR score>2.518 (62%)2 (13%)+828 (65%) Genotypic consequence of staying on a failing regimen (N=44) Results PPV: 31.0% 95%CI:

VF+VF-Total IF IF Total Test Characteristics of WHO- IF criteria to detect VF Sensitivity: 22.8% (95% CI: ) Specificity: 93.8% (95% CI: ) Mutation (Mut) Mut at time VF detectedMut during study Mut at end of study VF at enrollment (N=29) VF during study (N=15)(N=44) NRTI MUTATIONS M18425 (86%)8 (53%)+740 (91%) Any TAMS16 (55%) (66%) 1 TAM608 2 TAMs6011 ≥ 3 TAMS /Q151M2 (7%)0+57 (16%) K65R/70E4 (14%)0+04 (9%) TDF resistance6 (21%)0+915 (35%) NNRTI MUTATIONS K103N7 (24%)2 (13%)+312 (27%) Y181C15 (52%)2 (13%)+219 (43.%) G190A7 (24%)5 (33%)+618 (41%) K101E6 (21%)1 (7%)+613 (30%) ETR score>2.518 (62%)2 (13%)+828 (65%) Genotypic consequence of staying on a failing regimen (N=44) Results PPV: 31.0% 95%CI:

VF+VF-Total IF IF Total Test Characteristics of WHO- IF criteria to detect VF Sensitivity: 22.8% (95% CI: ) Specificity: 93.8% (95% CI: ) Mutation (Mut) Mut at time VF detectedMut during study Mut at end of study VF at enrollment (N=29) VF during study (N=15)(N=44) NRTI MUTATIONS M18425 (86%)8 (53%)+740 (91%) Any TAMS16 (55%) (66%) 1 TAM608 2 TAMs6011 ≥ 3 TAMS /Q151M2 (7%)0+57 (16%) K65R/70E4 (14%)0+04 (9%) TDF resistance6 (21%)0+915 (35%) NNRTI MUTATIONS K103N7 (24%)2 (13%)+312 (27%) Y181C15 (52%)2 (13%)+219 (43.%) G190A7 (24%)5 (33%)+618 (41%) K101E6 (21%)1 (7%)+613 (30%) ETR score>2.518 (62%)2 (13%)+828 (65%) Genotypic consequence of staying on a failing regimen (N=44) Results PPV: 31.0% 95%CI:

VF+VF-Total IF IF Total Test Characteristics of WHO- IF criteria to detect VF Sensitivity: 22.8% (95% CI: ) Specificity: 93.8% (95% CI: ) Mutation (Mut) Mut at time VF detectedMut during study Mut at end of study VF at enrollment (N=29) VF during study (N=15)(N=44) NRTI MUTATIONS M18425 (86%)8 (53%)+740 (91%) Any TAMS16 (55%) (66%) 1 TAM608 2 TAMs6011 ≥ 3 TAMS /Q151M2 (7%)0+57 (16%) K65R/70E4 (14%)0+04 (9%) TDF resistance6 (21%)0+915 (35%) NNRTI MUTATIONS K103N7 (24%)2 (13%)+312 (27%) Y181C15 (52%)2 (13%)+219 (43.%) G190A7 (24%)5 (33%)+618 (41%) K101E6 (21%)1 (7%)+613 (30%) ETR score>2.518 (62%)2 (13%)+828 (65%) Genotypic consequence of staying on a failing regimen (N=44) Results PPV: 31.0% 95%CI:

Conclusions WHO criteria for immunologic failure have poor sensitivity (22.8%) for detecting virologic failure. By using these criteria, a notable proportion of patients would be continued on first line therapy that they are already failing. Implications for second line therapy: at 18 months of f/u, 35% patients had predicted resistance tenofovir 65% patients had predicted resistance to etravirine. Given the poor PPV (31%), relying on CD4 count data alone would lead to a substantial number of unnecessary switches to second-line HAART. Universal access to VL monitoring would avoid costly switches to second-line HAART and preserve future therapeutic options.