CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

THURSDAY, FEBRUARY 26, 2015 Session P-L4 Poster Session

Poster Hall

2:30 pm– 4:00 pm HIV Drug Resistance: Global Perspective and Clinical Implications 604 A Clinical Prediction Rule for PI Resistance in Resource-Limited Settings

Karen Cohen 1 ; Annemie Stewart 1 ; Andre P. Kengne 1 ; Rory F. Leisegang 1 ; Marla Coetsee 2 ; Shavani Maharaj 2 ; Liezl Dunn 2 ; Graeme Meintjes; Gert U. van Zyl 3 ; Gary Maartens 1 1 University of Cape Town, Cape Town, South Africa; 2 Aid for AIDS Management (Pty) Ltd, Cape Town, South Africa; 3 University of Stellenbosch, Cape Town, South Africa Background: Although virological failure is common in adults on second-line ART in resource limited settings, major protease inhibitor (PI) resistance mutations occur infrequently. Therefore, empiric switches to salvage therapy would waste resources. Resistance testing identifies patients needing salvage therapy, but is expensive and access is limited. Therefore, a clinical prediction rule (CPR) to rationalise access to resistance testing would be a valuable tool. Methods: We identified predictors of major PI resistance mutations in a large South African cohort. We included adults with virological failure and ≥ 4 months exposure to lopinavir/atazanavir-based ART. PI resistance was defined as ≥ 1 major resistance mutations to current PI. We constructed a multivariate logistic regression model including age, sex, PI duration, adherence by pharmacy claims, concomitant CYP3A4-inducing drugs and viral load (VL) at time of genotyping as candidate predictors based on an a priori decision. We selected variables included in the CPR using a stepwise approach. We internally validated by bootstrapping. We categorised included variables, and assigned points to each level based on adjusted beta coefficients. Results: There was PI resistance in 146/339 (43%) patients. Median age was 42 years (IQR 36 to 47), 211 (62%) were female, and 309 (91%) and 30 (9%) were on ritonavir-boosted lopinavir and atazanavir respectively. Median PI duration was 2.6 years (IQR 1.6 to 4.7). Median adherence was 97% (IQR 73 to 100) and 9% took concomitant inducing drugs. Median log VL was 4.9 (IQR 4.3 to 5.4). Presence of major PI resistance mutations were associated with age (adjusted odds ratio (aOR) for 10 year increase 1.9 (95% CI 1.4 to 2.6)); PI duration (aOR per year 1.1 (95% CI 1.0 to 1.3)); and adherence (aOR per 10% increase 1.2 (95% CI 1.1 to 1.3)). There was no association with sex, inducer exposure and VL. We included age, PI duration and adherence in the CPR. Area under the ROC curve was 0.736 (95% CI 0.683 to 0.789) before and 0.739 (95% CI 0.736 to 0.742) after bootstrapping. The model had acceptable calibration. The optimal cut point corresponded to a score of 8/15 (75% sensitivity and 67% specificity).

Poster Abstracts

Table: Clinical prediction rule for major PI resistance mutations Conclusions: Older patients with high adherence and prolonged PI exposure are most likely to benefit from resistance testing. The CPR may be a useful tool to rationalise patient selection for resistance testing in resource limited settings, but requires external validation 605 Baseline Low-Frequency HIV-1 Variants Do Not Predict Virologic Failure to RPV/FTC/TDF Background: Rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) is currently approved for use in HIV-1 treatment-naïve adults with HIV-1 RNA ≤ 100,000 c/mL due to increased virologic failure with resistance development in patients with high baseline viral load (BL VL). At Week 96 in the phase 3b STaR study (GS-US-264-0110; RPV/FTC/TDF vs. efavirenz/ FTC/TDF in treatment-naïve adults with no BL VL restriction), 5.3% of patients on RPV/FTC/TDF developed resistance mutations by population sequencing (9.0% BL VL >100,000 c/ mL vs. 3.5% BL VL ≤ 100,000 c/mL). Deep sequencing was performed to assess the potential clinical impact of pre-existing minority variants in RPV/FTC/TDF-treated patients with high BL VL. Methods: Deep sequencing (Illumina MiSeq) was performed on baseline and virologic failure (VF) samples for 24 RPV/FTC/TDF-treated patients in the resistance analysis population (RAP; patients with HIV-1 RNA ≥ 400 c/mL at VF, discontinuation, or Weeks 48 or 96). Baseline samples from 44 non-RAP RPV/FTC/TDF-treated BL VL and BL CD4 matched control patients, including all 29 with BL VL ≥ 500,000 c/mL, were also analyzed. Deep sequencing results ( ≥ 1% cutoff) were compared to population sequencing. Results: Baseline NRTI- or NNRTI-associated mutations were detected in 29% (7/24) of RAP isolates and 27% (12/44) of controls by deep sequencing. Study exclusion mutations were detected at low frequencies in 4 RAP patients (BL VL >100,000 c/mL: E138K, H221Y n=1 each; BL VL ≤ 100,000 c/mL: M184V, E138G n=1 each). While all 4 patients developed NRTI- and/or NNRTI-associated mutations in their HIV-1 at VF, none of these same mutations were detected except for 1 patient with 1.17%M184V at baseline who had >99% Danielle P. Porter 1 ; Martin Däumer 2 ; AlexanderThielen 2 ; Michael D. Miller 1 ; Kirsten L.White 1 1 Gilead Sciences, Inc., Foster City, CA, US; 2 Seq-IT GmbH & Co KG, Kaiserslautern, Germany

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CROI 2015