CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

among this group. For the 13%with PI resistance, accessible and effective agents should be considered.

542 LOW PREVALENCE OF INTEGRASE STRAND TRANSFER INHIBITORS RESISTANCE ACROSS BOTSWANA Simani Gaseitsiwe 1 , Sikhulile Moyo 1 , Melissa Zahralban-Steele 2 , Dorcas Maruapula 1 , Baitshepi Mokaleng 1 , Terence Mohammed 1 , Shenaaz El-Halabi 3 , Elliot G. Raizes 4 , Tendani Gaolathe 1 , Shahin Lockman 2 , Max Essex 2 , Vlad Novitsky 2 1 Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana, 2 Harvard University, Cambridge, MA, USA, 3 Botswana Ministry of Health, Gaborone, Botswana, 4 CDC, Atlanta, GA, USA Background: The use of dolutegravir (DTG)-based first-line combination antiretroviral therapy (cART) is now recommended by the WHO HIV treatment guidelines. The Botswana national HIV treatment program started using DTG-based first-line cART in June 2016. As the previous HIV salvage regimen in Botswana has used raltegravir, a first generation integrase strand transfer inhibitor (INSTI), it is important to monitor the population prevalence of INSTI resistance mutations. Methods: Blood samples were collected from HIV-positive participants in the Botswana Combination Prevention Project (BCPP) residing in 25 communities representing southern, northern, and eastern Botswana in 20132015. A long-range HIV genotyping protocol was applied. INSTI resistance mutations were analyzed according to the IAS-USA 2017 list with the addition of H51Y and G118R mutations described recently. All viral sequences were screened for hypermutations (HM). Mutations in sequences with adjusted HM rate >=2% were considered to be generated by HM, and were not counted toward drug- resistant INSTI. Results: After adjusting for HMs, a total of 2,342 (979 southern, 916 eastern and 447 northern) unique sequences, were included in analysis of INSTI resistance mutations. Among 2,241 individuals with ART data available, 1,583 (71%; 95% CI 6973%) were receiving cART and 1,520 of them (96%; 95% CI 9597%) had HIV-1 RNA 400 copies/mL. The overall prevalence of INSTI resistance mutations was 2.0% (47 of 2,342; 95% CI 1.52.7%). Prevalence of INSTI mutations was similar across the country regions1.8%, 2.2% and 2.0% in the South, East, and North, respectively. Among a subset of 16 communities with genotyping density 10%, median (IQR) prevalence of INSTI was 2% (1.1% to 2.7%) ranging from 0 to 3.8%. The table demonstrates the prevalence of identified INSTI mutations among the analyzed 2,342 BCPP participants. Conclusion: This is the first large-scale study of HIV-1C mutations associated with INSTI resistance in Africa. A low prevalence of INSTI resistance mutations at 2% across the country suggests minimal impact of population exposure to raltegravir and provides a strong rationale for use of DTG as the first-line cART regimen. Monitoring of the prevalence of INSTI resistance mutations is warranted to ensure effectiveness of the first line cART regimen.

543 HIGH LEVEL RESISTANCE TO DOLUTEGRAVIR (DTG) AFTER EMERGENCE OF T97A MUTATION Safia S. Kuriakose 1 , Jomy M. George 2 , Nicola Dee 1 , Pam Stoll 2 , Brian K. Agan 3 , Robin L. Dewar 1 , Alice K. Pau 2 , Frank Maldarelli 4 1 Leidos Biomedical Research, Inc, Frederick, MD, USA, 2 NIH, Bethesda, MD, USA, 3 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 4 National Cancer Institute, Frederick, MD, USA Background: The IN mutation T97A is a major accessory mutation that may emerge with viral rebound during DTG salvage therapy, often with additional drug resistance mutations (DRMs). The contribution of T97A alone to in vivo emergence of INSTI resistance, especially DTG, is not well described. We report 2 patients with extensive ARV resistance who had INSTI DRMs (including G140S, Q148H) prior to switching to DTG. Both had emergence of the T97A mutation as the sole new DRM, leading to >10-fold increases in phenotypic resistance to DTG. Methods: Both patients were enrolled in a clinical study investigating ART failure (NCT 01976715). Samples were analyzed using commercial phenotyping (Monogram) and genotyping (TRUGENE) assays, and in-house genotyping. Selected samples were subjected to next generation sequencing (NGS, Illumina) with limit of detection of DRM of c. 1%. HIV sequences were analyzed (Stanford/ ANRS algorithms); phenotyping analyses (PhenoSense Integrase GT™) and coreceptor tropicity (Monogram) were performed. Results: Pt 1 - 51 yr-old man diagnosed with HIV in 1989, with extensive prior ART including RAL. At enrollment, he was on LPV/r+ATV+TDF/FTC with HIV-VL 136,476 c/mL. Genotypic testing revealed INSTI DRMs (G140S, Q148H). NGS did not detect other INSTI DRMs. Phenotypic testing showed partial sensitivity to DTG (4.61-fold change (FC) of IC50 from reference range) and R5-tropic HIV. Within 3 months of ART change to DTG 50mg bid+DRV/r+TDF/FTC+MVC, VL was <50 c/ml. After 6 months, however, VL rebounded to 1,638 c/mL despite ARV levels consistently within therapeutic range. Resistance testing revealed high-level phenotypic resistance to DTG (inc. from 4.61 to 66 FC). T97A was the only new DRM (Table 1). Pt 2 - 52 yr-old man diagnosed with HIV in 1993, with extensive prior ART including INSTIs. Resistance testing revealed partial sensitivity to DTG (6.7 FC) and INSTI DRMs (E138T, G140S, Q148H). NGS did not detect other INSTI DRMs. After restarting a regimen of DTG/ABC/3TC+TDF for 2 months, VL was 44,186 copies/mL. Resistance testing revealed high-level phenotypic resistance to DTG (inc. from 6.7 to 119 FC). T97A was the only new DRM (Table 1). Conclusion: Isolated emergence of the T97A mutation led to high level DTG resistance in these 2 patients with prior INSTI resistance. Rebound viremia, even after suppression, with > 10 fold increases in DTG IC50 may emerge with T97A in patients with reduced INSTI susceptibility and Q148H + G140S containing genotypes.

Poster Abstracts

CROI 2018 199