CROI 2015 Program and Abstracts

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Oral Abstracts

Methods: Plasma samples were obtained at the HPTN 061 enrollment visit from the 169 HIV-infected men described above. Samples were tested for the presence of 15 ARV drugs using a qualitative assay based on high-resolution mass spectrometry. Self-reported data on prior and current ARV drug use for pre-exposure prophylaxis, post-exposure prophylaxis, and ARV treatment were collected in the HPTN 061 study. Results: ARV drugs were detected in 60 (35.5%) of the 169 men, including 27 (56.3%) of the 48 men who had drug-resistant HIV. Eighteen (37.5%) of those 48 men had at least one ARV drug detected that was not consistent with their drug resistance mutations. Unusual combinations of ARV drugs were detected in some samples. Thirty-one of the 137 men who reported no prior or current ARV drug use had drug-resistant HIV; based on these data alone (self-reported ARV drug use and resistance testing), the estimated rate of transmitted drug resistance (TDR) was 22.6%. However, 14 of the men with drug-resistant HIV also had at least one ARV drug detected. After excluding those men, the estimated rate of TDR was 12.4%. Five (29%) of the 17 men with TDR had multi-class drug resistance. Conclusions: ARV drug testing can provide important information relevant to the emergence and transmission HIV drug resistance. In addition to the high levels of drug resistance previously observed in this cohort, ARV drug testing indicated that a significant portion of the men were at risk of acquiring additional drug resistance mutations. ARV drug testing also provided a more accurate estimate of TDR by identifying men who were using ARV drugs but chose not to disclose this to study staff. These findings demonstrate the benefit of Background: HIV resistance testing in HAART patients experiencing low-level viremia (LLV, 50-999 HIV-RNA copies/mL) predicts the risk of subsequent virologic failure (VF, ≥ 1000 copies/ml). Suboptimal plasma drug levels can arise as a result of poor adherence and/or pharmacokinetic issues. Here, our aimwas to evaluate whether retrospective analysis of plasma levels also provides insight into patient outcomes after experiencing LLV. Methods: The first documented LLV episode of 2176 patients was analyzed. A total of 328 consenting patients with drug levels, genotypic resistance data and with follow-up clinical data while on constant therapy available were eligible. Untimed plasma drug levels (UDL) of PIs and NNRTIs in the sample corresponding to the first LLV episode were measured by HPLC-tandemMS. Drug levels were categorized as ‘therapeutic’ or ‘suboptimal’ based on target trough concentrations from DHHS guidelines. Resistance was assessed using the Stanford algorithm (GSS, corresponding to the number of ‘active’ drugs prescribed). Time to VF after LLV was evaluated by Kaplan–Meier analysis and Cox proportional hazards regression. Results: 78 of 328 patients (24%) had suboptimal drug levels at LLV, compared with 63 (19%) having GSS<3. Both suboptimal UDL and GSS<3 independently increased the risk of future pVL >1000. Within a year, 56/78 (72%) patients with suboptimal UDL had failed, compared to 45/63 (71%) with GSS <3 and to 103/206 (50%) with both optimal GSS and UDL. Of those with suboptimal UDL, 43/78 (55%) had undetectable levels of PI/NNRTI, with most (81%) failing by one year. Only 18 patients had both suboptimal UDL and GSS<3. In the adjusted multivariable model, variables associated with VF were suboptimal UDL (Adjusted Hazard Ratio, AHR 2.9, 95%CI 2.0-4.2, p<0.001), female gender (AHR 1.9, 95%CI 1.3-2.9, p=0.001), GSS<3 (AHR 1.5, 95%CI 0.9-2.3, p=0.098) and being HAART-naïve (AHR 1.7, 95%CI 1.1-2.7, p=0.031). When UDL and GSS categories were combined, the lowest VF was found for optimal UDL &GSS ≥ 3 (P<0.001). Numerous sensitivity analyses confirmed these findings. Conclusions: A single untimed drug level (UDL) and GSS independently predict subsequent VF, with suboptimal UDL having a greater hazard than GSS<3, especially if drug levels are undetectable. Together, UDL and GSS can explain a higher proportion of treatment failures than either measure alone. These results could justify the potential investigation of UDL in prospective of management of LLV. 118 Pretreatment HIV Drug Resistance Increases Regimen Switch in Sub-Saharan Africa Tamara Sonia Boender 1 ; Bernice M. Hoenderboom 1 ; Kim C. Sigaloff 1 ; MaureenWellington 2 ; Margaret Siwale 3 ; Cissy M. Kityo 4 ; Alani Sulaimon Akanmu 5 ; Mariette E. Botes 6 ;Tobias F. Rinke deWit 1 On behalf of the PASER Study Group 1 Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands; 2 Newlands Clinic, Harare, Zimbabwe; 3 Lusaka Trust Hospital, Lusaka, Zambia; 4 Joint Clinical Research Centre, Kampala, Uganda; 5 Lagos University Teaching Hospital, Lagos, Nigeria; 6 Muelmed Hospital, Pretoria, South Africa Background: After the successful scale-up of antiretroviral therapy (ART) in Africa, there are concerns about emerging drug-resistant HIV and an increasing need for more costly second-line regimens. We investigated the impact of pretreatment drug resistance (PDR) on 2 and 3 year ART outcomes and switch to second-line in the first 3 years of ART within the Pan-African Studies to Evaluate Resistance Monitoring (PASER-M) cohort. Methods: The PASER-M cohort followed HIV-1 infected individuals initiating first-line ART for 2 years (13 sites) or 3 years (5 sites) in 6 African countries. Viral load (VL) and pol genotypic testing (if VL>1000 cps/ml) was performed at ART initiation and annually thereafter. PDR was defined as a decreased susceptibility to at least one prescribed drug, using the Stanford algorithm and IAS-USA mutation list. The effect of PDR on (I) switch to second-line with acquired drug resistance, (II) virological failure (VL>400 c/ml) and (III) acquired drug resistance during the first 3 years of ART was assessed using cumulative incidence plots, multivariate cox-models and multilevel logistic regression. Unnecessary switch was defined as switch with VL<1,000 cps/ml or VL>1,000 cps/ml with wild-type virus. Results: For 2,579 (94.2%) of 2,737 participants genotypes were available at ART initiation; in 5% (n=139) PDR was present. After 3 years, 112 (4.3%) participants had switched to second-line regimen of whom 78 (69.6%) had VL results and genotypes available; 33.3% (n=26) switched unnecessarily. Most switches with drug resistance took place after 1 year of ART (figure). Incidence density of switch was 1.1 per 100 person-years. PDR increased the risk of: (I) switch with drug resistance, subhazard ratio 7.8 (95%CI 3.9-15.6) during 3 years; (II) virological failure, odds ratios (OR) 2.9 (95%CI 1.4-5.8) after 2 years and 2.8 (95%CI 1.1-7.2) after 3 years, and (III) acquired drug resistance, OR 2.5 (95%CI 1.2-5.4) after 2 years and OR 5.0 (95%CI 1.8-14.3) after 3 years of first-line ART. PDR was not associated with mortality or new AIDS events. combining HIV drug resistance testing with ARV drug testing for the analysis of HIV drug resistance. 117 Untimed Drug Levels and Resistance in Patients Experiencing Low-Level HIV Viremia Alejandro Gonzalez-Serna ; Luke C. Swenson; Adriana Nohpal; BirgitWatson; Kate Auyeung; Julio Montaner; Richard Harrigan BC Centre for Excellence in HIV/AIDS, Vancouver, Canada

Oral Abstracts

158

CROI 2015