Safety Profile of HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 24 Analysis J Lalezari 1 , GH Latiff 2 , C Brinson 3 , J Echevarría 4 , S Treviño-Pérez 5 , JR Bogner 6 , D Stock 7 , SR Joshi 7 , GJ Hanna 8 , M Lataillade 7 , for the AI438011 study team 1 Quest Clinical Research, San Francisco, CA, USA; 2 Maxwell Clinic, Durban, South Africa; 3 Central Texas Clinical Research, Austin, TX, USA; 4 Hospital Nacional Cayetano Heredia, Lima, Peru; 5 Mexico Centre for Clinical Research, Mexico City, Mexico; 6 Hospital of the University of Munich, Munich, Germany; 7 Bristol-Myers Squibb, Wallingford, CT, USA; 8 Bristol-Myers Squibb, Princeton, NJ, USA Max Lataillade, DO MPH Bristol-Myers Squibb Research and Development Wallingford CT 06492 USA Email: [email protected] Phone: 203-677-7991 Poster 1574 BACKGROUND ■ Despite the success of combination antiretroviral therapy, some HIV-positive patients may have limited treatment options owing to: — presence of viral mutants causing reduced antiretroviral (ARV) drug susceptibility — emergence of drug toxicities from long-term ARV therapy — contraindications from the need to manage associated co-infections and morbidities 1,2 ■ Consequently, there is a continued need to develop novel ARVs that have: — unique resistance profiles — well-tolerated safety profiles — limited or manageable drug–drug interactions ■ BMS-663068 is a prodrug metabolized to the active moiety BMS-626529 (Figure 1), a first-in-class attachment inhibitor that binds to HIV-1 gp120, preventing initial viral attachment and entry into the host CD4+ T cell (Figure 2) 3,4 ■ BMS-626529 has in vitro activity against HIV-1 viruses, with the exception of subtype AE and Group O 5 ■ By binding directly to the virus, BMS-626529 is not affected by co-receptor tropism and is therefore active against CCR5-, CXCR4- and dual-tropic (R5X4) strains of HIV-1 4,6-8 ■ BMS-626529 has a unique resistance profile with no in vitro cross-resistance to other classes of antiretrovirals 6 ■ AI438011 is an ongoing Phase IIb study investigating the efficacy, safety and dose response of BMS-663068 versus atazanavir/ritonavir (ATV/r) in HIV-1-infected, treatment-experienced subjects ■ Through Week 24, BMS-663068 + tenofovir-disoproxil fumarate (TDF) + raltegravir (RAL) demonstrated comparable efficacy to ATV/r + TDF + RAL (modified intent-to-treat SnapShot, Table 1) Gastrointestinal lumen BMS-663068 (prodrug) BMS-626529 (active moiety) BMS-626529 Blood plasma Alkaline phosphatase Figure 1. Conversion of BMS-663068 to BMS- 626529 Figure 2. BMS-626529 attachment inhibitor: Proposed mechanism of action Table 1. AI438011 efficacy summary: Week 24 SnapShot: modified intent-to-treat (Presented at CROI 2014 9 ) BMS-663068 + TDF + RAL ATV/r + TDF + RAL 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 HIV-1 RNA <50 c/mL, % 40 (80.0%) 34 (69.4%) 39 (76.5%) 36 (72.0%) 38 (74.5%) HIV-1 RNA ≥50 c/mL, % 8 (16.0%) 10 (20.4%) 11 (21.6%) 13 (26.0%) 9 (17.6%) No virologic data at Week 24 Discontinued due to adverse event or death, n (%) 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%) Discontinued for other reasons, n (%) 1 (2.0%) 3 (6.1%) 1 (2.0%) 0 2 (3.9%) Missing data during window but on-study, n (%) 0 0 0 0 0 ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Modified intent-to-treat population: all subjects receiving ≥1 dose of study drug. OBJECTIVES ■ To assess the safety and tolerability through Week 24 of BMS-663068, when combined with RAL and TDF, in HIV-1-infected subjects by measuring frequency of: — adverse events (AEs) — serious AEs (SAEs) and — AEs leading to discontinuation ACKNOWLEDGMENTS ■ We would like to thank all of the AI438011 clinical trial participants and their families ■ AI438011 Investigators: JD Altclas, PE Cahn, SH Lupo, MD Martins, AI Arango-Duque, OA Sussmann-Pena, G Amaya-Tapia, JF Andrade-Villanueva, ER Granados-Reyes, JG Sierra-Madero, SC Trevino-Perez, WM Casapia-Morales, JI Echevarria, JR Lama-Valdivia, MY Leon-Paredes, FC Mendo-Urbina, Y Pinedo-Ramirez, MR Salazar-Castro, R Bardinas-Rodriguez, C Brinson, E Dejesus, R Elion, J Ernst, J Feinberg, S Hassler, C Hicks, J Lalezari, AR Scribner, L Sloan, M Thompson, K Arastéh, J Bogner, J Rockstroh, A Stoehr, IG Diaconescu, LJ Prisacariu, S Rugina, OA Tsybakova, EE Voronin, AA Yakovlev, NG Zakharova, J Fourie, D Johnson, R Kaplan, G Latiff, B Clotet ■ Bristol-Myers Squibb: A Rightmire, M DeGrosky, J Coumbis, N Ray, N Cusack, M Krystal, C Hwang and T Correll ■ Other: P Lill and J Riefler (ICON CRO) ■ Professional medical writing and editorial assistance was provided by MediTech Media and was funded by Bristol-Myers Squibb REFERENCES 1. Wainberg M et al . JAMA 1998; 279:1977–1983. 2. Wittcop L et al . Lancet Infect Dis 2011; 11:363–371. 3. Brown J et al . J Pharm Sci 2013: 102:1742–1512 4. Langley DL et al . Manuscript in development 5. Varghese V et al . J Acquir Immune Defic Syndr 2009; 52:309–315. 6. Li Z et al . AAC 2013; 57:4172–4180. 7. Nowicka-Sans B et al . AAC 2012; 56:3498–3507. 8. Ray N et al . JAIDS 2013; 64:7–15. 9. Lalezari J et al . CROI 2014: Oral Abstract 86. 10. Bristol-Myers Squibb. Reyataz prescribing information. 2013. Available at: http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed April 2014. CONCLUSIONS ■ BMS-663068 was generally well tolerated across all arms: — no related SAEs or AEs leading to discontinuation — no dose-related safety signals ■ Across the BMS-663068 arms, there were no trends for Grade 2–4 AEs or Grade 3–4 clinical laboratory abnormalities ■ These results support continued development of BMS-663068 ■ An analysis of BMS-663068 efficacy by subgroup through Week 24 will be presented on Thursday, October 9 th at 3pm by Brinson et al (Oral 540) METHODS AI438011 study design ■ Phase IIb, randomized, active-controlled, blinded-to-BMS-663068 dose trial (NCT01384734) ■ Consisted of a 7-day elective monotherapy substudy and the main study (Figure 3) ■ For the main study, subjects were randomized 1:1:1:1:1 into five treatment arms: four treatment groups of BMS-663068 (400 mg twice daily [BID], 800 mg BID, 600 mg once daily [QD], or 1200 mg QD), and a reference group (ATV/r 300/100 mg QD), each with a backbone of RAL 400 mg BID + TDF 300 mg QD (Figure 3) Primary endpoint Week 24 BMS - Day 1 Week 8 Data monitoring committee assessment BMS-663068 400 mg BID + RAL + TDF N=50 BMS-663068 800 mg BID + RAL + TDF N=50 BMS-663068 600 mg QD + RAL + TDF N=50 Primary study - start of combination therapy BMS-663068 monotherapy substudy: 10 patients per study arm Long-term follow-up through Week 48/96 Week 48/96 BMS-663068 1200 mg QD + RAL + TDF N=50 ATV/r 300/100 mg QD + RAL + TDF N=50 Partial blind* Figure 3. AI438011 study design * Blinded to BMS-663068 dose. ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Eligibility criteria ■ Main inclusion criteria: — antiretroviral treatment-experienced (defined as current or previous exposure to ≥1 antiretroviral for ≥1 week) — plasma HIV-1 RNA ≥1000 c/mL — CD4+ T-cell count >50 cells/mm 3 — susceptibility to RAL, TDF and ATV — BMS-626529 IC 50 <100 nM as determined by screening Phenosense ® entry assay (Monogram Biosciences - LabCorp) — no other significant abnormalities on medical history, physical examination, 12-lead electrocardiograms (ECGs), and clinical laboratory evaluations — aged 18–49 years — body mass index 18–32 kg/m 2 ■ Main exclusion criteria: — pregnancy or breast feeding — any significant acute or chronic medical illness — liver enzymes (aspartate aminotransferase [ALT]/alanine aminotransferase [AST]) >5 times the upper limit of normal — positive blood screen for hepatitis B surface antigen or hepatitis C antibodies/RNA Assessments ■ Safety assessments included: — vital signs and physical examinations — recording of AEs (SAEs, AEs and Centers for Disease Control Class C AIDS events) — measurements of changes in fasting lipids — laboratory abnormalities and ECG measurements ■ Assessments were performed at Weeks 4, 8, 12, 16, 20, 24 ■ AEs were coded according to MedDRA version 15.1 and the severity and relationship to study drug was assessed by the corresponding investigator RESULTS Baseline characteristics ■ Baseline demographic and disease characteristics were broadly similar across all treatment groups (Table 2) — Median age range was 37–40 years; 60.0% male — 66.0% of subjects had HIV-1 subtype B — Median baseline HIV-1 RNA: 4.85 log 10 copies/mL — Median baseline CD4+ T-cell count: 229.5 cells/µL — ~ 50.0% of subjects had at least one major protease inhibitor (PI), nucleoside reverse transcriptase inhibitor or non-nucleoside reverse transcriptase inhibitor resistance-associated mutation at baseline (M184V/I, 31.0%; K103N, 29.0%; thymidine analogue mutations, 13.0%; major PI mutations, 2.0%) Table 2. Baseline characteristics BMS-663068 + TDF + RAL ATV/r + TDF + RAL 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Median age, years (range) 39 (22–57) 37(23–60) 40(26–58) 40 (20–67) 39 (20–68) Male, % 62.0% 57.1% 56.9% 68.0% 56.9% Race, % White 40.0% 38.8% 33.3% 32.0% 45.1% Black/African-American 28.0% 30.6% 31.4% 36.0% 25.5% Other 32.0% 30.6% 35.3% 32.0% 29.4% HIV subtype, n (%) B 70.0% 59.2% 68.6% 64.0% 66.7% C 16.0% 24.5% 21.6% 20.0% 17.6% Other* 14.0% 16.2% 9.9% 16.0% 15.6% HIV-1 RNA Median, log 10 c/mL 4.97 5.01 4.88 4.78 4.78 ≥100,000 c/mL, % 46.0% 51.0% 45.1% 36.0% 35.3% CD4+ T-cell count Median, cells/μL 214 237 226 224 249 <200 cells/μL, % 38.0% 32.6% 41.2% 42.0% 37.3% * Majority of subjects within the “other” category reported themselves as multiracial. ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Subject disposition ■ 581 subjects enrolled, 254 randomized and 251 treated (Figure 4) ■ Screen failures were primarily due to failure to meet study criteria; most common reasons (not mutually exclusive) were: — a screening plasma HIV-1 RNA of <1000 copies/mL — failure of the resistance assay(s) to provide a genotypic and/or phenotypic result for ≥1 of the study drugs ■ Of those receiving treatment, 32/200 (16.0%) across the BMS-663068 arms and 9/51 (17.6%) in the ATV/r arm failed to complete 24 weeks’ treatment (Figure 4) BMS-663068 (400 mg BID) + TDF + RAL Participated, n=7 Participated, n=5 Participated, n=10 Participated, n=10 BMS-663068 (800 mg BID) + TDF + RAL BMS - BMS-663068 (600 mg QD) + TDF + RAL BMS-663068 (1200 mg QD) + TDF + RAL Randomized (n=254) Assessed for eligibility (N=581) Randomized, n=52 Treated, n=50* Randomized, n=50 Treated, n=49 † Randomized, n=51 Treated, n=51 Randomized, n=50 Treated, n=50 Randomized, n=51 Treated, n=51 Ongoing at time of analysis (n=44 ) Ongoing at time of analysis (n=38) Ongoing at time of analysis (n=44) Ongoing at time of analysis (n=42) Ongoing at time of analysis (n=42) Discontinued (n=6) 1 adverse event 1 withdrew consent 2 lost to follow-up 1 poor/ non-compliance 1 other Discontinued (n= 11) 2 adverse events 2 withdrew consent 2 pregnancies 1 no longer met study criteria 3 lack of efficacy 1 poor/ non-compliance Discontinued (n=7) 1 pregnancy 2 lost to follow-up 1 no longer met study criteria 2 poor/ non-compliance 1 other Discontinued (n=8) 1 adverse event 1 withdrew consent 3 lost to follow-up 1 request to discontinue 1 no longer met study criteria 1 lack of efficacy Excluded (n=327) Did not meet inclusion criteria (n=303) Declined to participate (n=9) Lost to follow-up (n=3) Other reasons (n=11) Not reported (n=1) Discontinued (n=9) 2 adverse events 3 withdrew consent 2 pregnancies 1 administration- related 1 poor/ non-compliance ATV/r (300/100 mg QD) + TDF + RAL Monotherapy substudy Assigned to receive Primary study Figure 4. Subject disposition * Two subjects did not receive allocated intervention: one withdrew consent, one randomized in error; † One subject did not receive allocated intervention: withdrew consent. ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Table 3. Overall safety summary ■ A summary of AI438011 safety data through Week 24 is shown in Table 3 BMS-663068 + TDF + RAL ATV/r + TDF + RAL Total number of subjects, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 SAEs 4 (8.0%) 4 (8.2%) 3 (5.9%) 2 (4.0%) 5 (9.8%) Grade 2–4-related AEs 6 (12.0%) 3 (6.1%) 2 (3.9%) 6 (12.0%) 14 (27.5%) AEs leading to discontinuation 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%) AE, adverse event; SAE, serious AE; ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Grade 1–4 adverse events ■ A summary of Grade 1–4 AEs is shown in Table 4 ■ The most commonly reported AE across the BMS-663068 arms was headache (mostly Grade 1), which occurred in: — 28/200 (14.0%) of subjects in the BMS-663068 arms versus 5/51 (9.8%) in the ATV/r arm Table 4. All Grade 1–4 adverse events occuring in ≥10% of subjects BMS-663068 + TDF + RAL ATV/r + TDF + RAL Parameter, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Total subjects with an event 44 (88.0%) 40 (81.6%) 41 (80.4%) 42 (84.0%) 48 (94.1%) Infections and infestations 32 (64.0%) 28 (57.1%) 28 (54.9%) 26 (52.0%) 31 (60.8%) Urinary tract infection 4 (8.0%) 8 (16.3%) 4 (7.8%) 5 (10.0%) 3 (5.9%) Nasopharyngitis 6 (12.0%) 3 (6.1%) 6 (11.8%) 3 (6.0%) 4 (7.8%) Bronchitis 4 (8.0%) 1 (2.0%) 4 (7.8%) 5 (10.0%) 1 (2.0%) Herpes zoster 2 (4.0%) 5 (10.2%) 1 (2.0%) 0 0 Gastrointestinal disorders 16 (32.0%) 16 (32.7%) 15 (29.4%) 20 (40.0%) 19 (37.3%) Diarrhea 7 (14.0%) 4 (8.2%) 6 (11.8%) 4 (8.0%) 8 (15.7%) Nausea 3 (6.0%) 3 (6.1%) 3 (5.9%) 5 (10.0%) 6 (11.8%) Nervous system disorders 16 (32.0%) 9 (18.4%) 11 (21.6%) 11 (22.0%) 13 (25.5%) Headache 11 (22.0%) 4 (8.2%) 7 (13.7%) 6 (12.0%) 5 (9.8%) General disorders and administration site conditions 6 (12.0%) 3 (6.1%) 4 (7.8%) 8 (16.0%) 7 (13.7%) Fatigue 2 (4.0%) 1 (2.0%) 1 (2.0%) 5 (10.0%) 3 (5.9%) ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Serious adverse events ■ SAEs were reported in 13/200 (6.5%) subjects across the BMS-663068 treatment arms and 5/51 (9.8%) in the ATV/r arm (Table 5) ■ Most were secondary infections and none were related to BMS-663068 or ATV/r ■ Through Week 24, no deaths occurred Table 5. Serious adverse events* BMS-663068 + TDF + RAL ATV/r + TDF + RAL Parameter, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Total subjects with an event 4 (8.0%) 4 (8.2%) 3 (5.9%) 2 (4.0%) 5 (9.8%) Infections and infestations 2 (4.0%) 2 (4.1%) 2 (3.9%) 1 (2.0%) 3 (5.9%) Injury, poisoning and procedural complications 1 (2.0%) 0 1 (2.0%) 1 (2.0%) 0 Musculoskeletal and connective tissue disorders 0 1 (2.0%) 0 1 (2.0%) 0 Gastrointestinal disorders 0 0 0 0 1 (2.0%) Hepatobiliary disorders 0 0 0 0 1 (2.0%) Nervous system disorders 0 0 0 0 1 (2.0%) Pregnancy, puerperium and perinatal conditions 0 1 (2.0%) 0 0 0 Renal and urinary disorders 0 1 (2.0%) 0 0 0 Respiratory, thoracic and mediastinal disorders 1 (2.0%) 0 0 0 0 * A single patient may have had more than one event. ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Grade 2–4 related adverse events ■ Across the BMS-663068 arms, 17/200 (8.5%) subjects had Grade 2–4-related AEs; however most were single instances with no relationship to dose (Table 6) ■ In the ATV/r arm, 14/51 (27.5%) subjects had Grade 2–4-related AEs, which were mostly gastrointestinal and hepatobiliary disorders associated with hyperbilirubinemia (Table 6) Table 6. Select Grade 2–4-related adverse events* BMS-663068 + TDF + RAL ATV/r + TDF + RAL Parameter, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Total subjects with Grade 2–4-related AEs 6 (12.0%) 3 (6.1%) 2 (3.9%) 6 (12.0%) 14 (27.5%) Gastrointestinal disorders 0 1 (2.0%) 0 2 (4.0%) 5 (9.8%) Hepatobiliary disorders 0 0 0 0 7 (13.7%) Hyperbilirubinemia 0 0 0 0 4 (7.8%) Jaundice 0 0 0 0 2 (3.9%) DILI 0 0 0 0 1 (2.0%) Nervous system disorders 0 1 (2.0%) 0 1 (2.0%) 2 (3.9%) Headache 0 1 (2.0%) 0 0 2 (3.9%) Renal and urinary disorders 0 1 (2.0%) 1 (2.0%) 0 0 Hematuria 0 0 1 (2.0%) 0 0 Proteinuria 0 0 1 (2.0%) 0 0 Acute renal failure 0 1 (2.0%) † 0 0 0 Injury and poisoning 1 (2.0%) 0 0 0 0 Overdose 1 (2.0%) 0 0 0 0 Skin and subcutaneous disorders 0 1 (2.0%) 0 0 0 Hyperhidrosis 0 1 (2.0%) 0 0 0 * Select events presented. A single patient may have had more than one event. † TDF induced acute renal failure. AE, adverse event; ATV/r, ritonavir-boosted atazanavir; BID, twice daily; DILI, drug-induced liver injury; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Adverse events leading to discontinuation ■ A summary of AEs leading to discontinuation is shown in Table 7 — No BMS-663068-related SAEs or AEs leading to discontinuation Table 7. Adverse events leading to discontinuation* BMS-663068 + TDF + RAL ATV/r + TDF + RAL Parameter, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Total subjects: AE leading to discontinuation 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%) Gastrointestinal disorders 0 0 0 0 2 (3.9%) Abdominal distention 0 0 0 0 1 (2.0%) Flatulence 0 0 0 0 1 (2.0%) Nausea 0 0 0 0 1 (2.0%) Infections 0 1 (2.0%) 0 1 (2.0%) 0 Bone tuberculosis 0 1 (2.0%) 0 0 0 Disseminated tuberculosis 0 0 0 1 (2.0%) 0 Hepatobiliary 0 0 0 0 1 (2.0%) Jaundice 0 0 0 0 1 (2.0%) Musculoskeletal 0 0 0 1 (2.0%) 0 Back pain 0 0 0 1 (2.0%) 0 Renal 0 1 (2.0%) 0 0 0 Acute renal failure 0 1 (2.0%) 0 0 0 Vascular 1 (2.0%) 0 0 0 0 Ischemia (likely related to cocaine use) 1 (2.0%) 0 0 0 0 * A single patient may have had more than one event. AE, adverse event; ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Grade 3–4 laboratory abnormalities ■ Across the BMS-663068 arms, no noticeable trend for Grade 3–4 lab abnormalities was observed (Table 8) — Grade 3–4 hematologic changes (neutropenia, 5/196 [2.6%]) were uncommon — Liver chemistry elevations (AST/ALT elevations, 2/196 [1.0%]) were uncommon ■ In the ATV/r arm 25/51 (49.0%) of subjects had elevations in total bilirubin, consistent with the known profile of ATV 10 Table 8. Select Grade 3–4 laboratory abnormalities BMS-663068 + TDF + RAL ATV/r + TDF + RAL Parameter, n (%) 400 mg BID N=50 800 mg BID N=49 600 mg QD N=51 1200 mg QD N=50 300 mg/100 mg QD N=51 Hematology Hemoglobin/hematocrit 0 0 0 0 0 Platelet 0 0 0 0 0 Neutrophils 1 (2.0%) 1 (2.0%) 2 (3.9%) 1 (2.0%) 0 Liver and kidney function Alkaline phosphatase 0 0 0 1 (2.0%) 0 Alanine aminotransferase 0 0 0 2 (4.0%) 1 (2.0%) Aspartate aminotransferase 0 1 (2.0%) 0 1 (2.0%) 0 Bilirubin 0 0 0 0 25 (50.0%) Estimated creatinine clearance 0 0 0 0 0 Other chemistry testing Creatinine kinase 0 1 (2.0%) 1 (2.0%) 1 (2.0%) 0 ATV/r, ritonavir-boosted atazanavir; BID, twice daily; QD, once daily; RAL, raltegravir; TDF, tenofovir-disoproxil fumarate. Changes from baseline in fasting lipids ■ No clinically significant changes in total cholesterol, low-density lipoprotein and triglycerides from baseline observed across the BMS-663068 arms (Figure 5) — No dose relationship observed 400 mg BID 800 mg BID 600 mg QD 1200 mg QD 300 mg/100 mg QD BMS-663068 + TDF + RAL ATV/r + TDF + RAL -60 -50 -40 -30 -20 -10 0 10 20 Mean (SE) change in fasting lipids from baseline, mg/dL Total cholesterol LDL Triglycerides Figure 5. Mean change in total cholesterol, low-density lipoprotein and triglycerides from baseline through Week 24 ATV/r, ritonavir-boosted atazanavir; BID, twice daily; LDL, low-density lipoprotein; QD, once daily; RAL, raltegravir; SE, standard error; TDF, tenofovir-disoproxil fumarate. IDWeek 2014 8–12 October 2014, Philadelphia, PA, USA