Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- Expert Faculty Debate the Evidence.2014
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In this downloadable slideset, Joseph J. Eron, Jr., MD, and Daniel Kuritzkes, MD, review key data on the evolving use of INSTIs in patients beginning HIV therapy. Format: Microsoft PowerPoint (.ppt) File size: 2.29 MB
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Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy- Expert Faculty Debate the Evidence.2014
- 1. Joseph J. Eron, Jr., MD University of North Carolina Chapel Hill, North Carolina Daniel R. Kuritzkes, MD Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Expert Faculty Debate the Evidence This activity is supported by an educational grant from ViiV
- 2. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
- 3. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Program Director Joseph J. Eron, Jr., MD Professor of Medicine and Epidemiology University of North Carolina School of Medicine Director, AIDS Clinical Trials Unit University of North Carolina Chapel Hill, North Carolina Faculty Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts
- 4. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Additional Faculty Contributing to Content Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California Sally Hodder, MD Director, Clinical Translation Science Institute Professor of Medicine West Virginia University Morgantown, West Virginia Kathleen E. Squires, MD W. Paul and Ida H. Havens Professor of Infectious Diseases Director, Division of Infectious Diseases Sidney Kimmel Medical College of Thomas Jefferson University Philadelphia, Pennsylvania
- 5. Introduction to the Use of Integrase Inhibitor–Based Regimens in First-line Therapy
- 6. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? The Current Landscape: DHHS 2014 Recommended First-line ART Regimens IAS-USA guidelines panel recommend similar approach Guidelines published before approval of DTG/ABC/3TC single-tablet regimen DHHS Guidelines. May 2014. Günthard HF, et al. JAMA. 2014;312:410-425. Class All Pts, Regardless of BL VL or CD4+ Count Pts With Pre-ART VL < 100,000 c/mL NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC ATV/RTV + ABC/3TC* INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC *Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3 .
- 7. Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Current Evidence on Integrase Inhibitors in First-line Therapy
- 8. Raltegravir
- 9. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? STARTMRK: Final 5-Yr Data Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. 281 282 100 80 60 40 20 0 HIV-1RNA<50c/mL(%) 0 48 72 96 120 144 Wks RAL EFV Pts at Risk, n 281 282 278 282 280 281 281 282 277 281 280 281 86 82 81 79 75 69 281 282 192 76 67 24012 216 71 61 277 282 279 279 24 279 282 168 281 282 RAL + TDF/FTC EFV/TDF/FTC 250 243 400 300 200 100 50 0 ChangeFromBaseline CD4+CellCount(cells/mm3 ) 0 48 72 96 120 144 Wks RAL EFV Pts at Risk, n 281 281 272 268 258 251 255 252 240 234 235 228 189 163 240 225 331 295 235 220 192 361 301 24012 216 374 312 227 218 222 212 24 266 266 168 231 224 RAL + TDF/FTC EFV/TDF/FTC 350 250 150
- 10. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? ACTG 5257: ATV/RTV vs RAL vs DRV/RTV in Treatment-Naive Pts Randomized, open-label phase III trial Primary endpoints – VF: confirmed HIV-1 RNA > 1000 c/mL (at or after Wk 16 and before Wk 24) or > 200 c/mL (at or after Wk 24) – TF: time to discontinuation of randomized component for toxicity Secondary composite endpoint: the earlier occurrence of either VF or TF Lennox JL, et al. Ann Intern Med. 2014;161:461-471. ART-naive pts with HIV-1 RNA ≥ 1000 c/mL (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in metabolic substudy, CV risk DRV/RTV 800/100 mg QD + TDF/FTC (n = 601) Wk 96 after last pt enrolled Regimen switch allowed for tolerability.
- 11. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? ACTG 5257: Cumulative Incidence of Virologic Failure at Wk 96 Lennox JL, et al. Ann Intern Med. 2014;161:461-471. Difference in 96-Wk Cumulative Incidence (97.5% CI) -20 0-10 10 20 ATV/RTV vs RAL 3.4% (-0.7% to 7.4%) DRV/RTV vs RAL 5.6% (1.3% to 9.9%) ATV/RTV vs DRV/RTV -2.2% (-6.7% to 2.3%) 1.00 0.75 0.50 0.25 0 CumulativeIncidence 0 Wks Since Study Entry 24 48 64 80 96 112 128 144 ATV/RTV RAL DRV/RTV
- 12. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Favors RAL Favors DRV/RTV Lennox JL, et al. Ann Intern Med. 2014;161:461-471. ACTG 5257: Cumulative Incidence of Tolerability Failure at Wk 96 Difference in 96-Wk Cumulative Incidence (97.5% CI) -20 0-10 10 20 ATV/RTV vs RAL 12.7% (9.4% to 16.1%) DRV/RTV vs RAL 3.6% (1.4% to 5.8%) ATV/RTV vs DRV/RTV 9.2% (5.5% to 12.9%) 1.00 0.75 0.50 0.25 0 CumulativeIncidence 0 Wks Since Study Entry 24 48 64 80 96 112 128 144 ATV/RTV RAL DRV/RTV
- 13. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Difference in 96-Wk Cumulative Incidence (97.5% CI) Favors RAL Favors RAL Favors DRV/RTV Lennox JL, et al. Ann Intern Med. 2014;161:461-471. ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure at Wk 96 -20 0-10 10 20 ATV/RTV vs RAL 15% (10.2% to 19.6%) DRV/RTV vs RAL 7.5% (3.2% to 11.8%) ATV/RTV vs DRV/RTV 7.5% (2.3% to 12.7%) 1.00 0.75 0.50 0.25 0 CumulativeIncidence 0 Wks Since Study Entry 24 48 64 80 96 112 128 144 ATV/RTV RAL DRV/RTV
- 14. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? ACTG 5257: Tolerability Failure at Wk 96 Lennox JL, et al. Ann Intern Med. 2014;161:461-471. Toxicity-Associated d/c of Randomized ART* ATV/RTV (n = 605) RAL (n = 603) DRV/RTV (n = 601) Any, n (%) 95 (15.7) 8 (1.3) 32 (5.3) Gastrointestinal, n 25 2 14 Hyperbilirubinemia, n 47 0 0 Other hepatic, n 4 1 5 Skin, n 7 2 5 Metabolic, n 6 0 2 Renal, n 4 0 0 Abnormal chemistry/hematology findings (excluding LFTs), n 0 0 2 Other, n 2 3 4 *Participants allowed to switch therapy for intolerable toxicity.
- 15. Elvitegravir
- 16. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 2. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124. Treatment naive; HIV-1 RNA ≥ 5000 copies/mL; any CD4+ cell count; susceptible to TDF, FTC, and EFV, or ATV; eGFR ≥ 70 mL/min Study 102[1] (N = 700) Study 103[2] (N = 708) EVG/COBI/TDF/FTC QD (n = 348) EFV/TDF/FTC QD (n = 352) EVG/COBI/TDF/FTC QD (n = 353) ATV/RTV + TDF/FTC QD (n = 355)
- 17. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? EVG/COBI Noninferior to EFV and to ATV/RTV, With TDF/FTC, Through Wk 144 Wk 48 Wk 144 EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) 80 75 0 20 40 60 80 100 88 84 Δ: 3.6% (-1.6 to 8.8) Δ: 4.9% (-1.3 to 11.1) 84 82 Wk 96 Δ: 2.7% (-2.9 to 8.3) EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Δ: 3.0% (-1.9 to 7.8) Δ: 1.1% (-4.5 to 6.7) Wk 48 Wk 144 78 75 0 20 40 60 80 100 90 87 Δ: 3.1% (-3.2 to 9.4) 83 82 Wk 96 Study 102[1] Study 103[2] 1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 2. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.
- 18. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Studies 102 and 103: Common Adverse Events Study 102[1] – More CNS effects, rash observed with EFV vs EVG/COBI – More nausea with EVG/COBI vs EFV Study 103[2] – More ocular icterus observed with ATV/RTV vs EVG/COBI – Common adverse events of EVG/COBI included nausea and diarrhea; frequency similar to that observed with ATV/RTV 1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
- 19. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Studies 102 and 103: Change in Serum Creatinine Through Wk 48 1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438. Study 102[1] Study 103[2] ChangeFromBaselinein SerumCreatinine(µmol/L) 20 15 10 5 0 -5 -10 0 2 4 8 12 16 24 32 40 48 EVG/COBI/TDF/FTC EFV/TDF/FTC SerumCreatinine ConcentrationChange(µmol/L) 20 15 10 5 0 -5 -10 0 2 4 8 12 16 24 32 40 48 EVG/COBI/TDF/FTC ATV/RTV + TDF/FTC Wks Wks
- 20. Dolutegravir
- 21. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Treatment-Naive Pts Randomized, double-blind, noninferiority phase III study Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 ART-naive pts, HIV-1 RNA ≥ 1000 copies/mL, HLA-B*5701 negative, CrCl > 50 mL/min (N = 833) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
- 22. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Wk 71% 63% 80% 72% 81% 88% Treatment CD4 Wk 144 ∆ From BL Adjusted Mean SE Difference in Response (95% CI) DTG + ABC/3TC (n = 414) 378.5 11.0 46.9 (15.6-78.1) P = .003EFV/TDF/FTC (n = 419) 331.6 11.6 BL 4 8 1216 24 32 40 14448 60 72 84 96 108 120 132 Adjusted treatment difference between groups at Wk 144: 8.3% (95% CI: 2.0-14.6; P = .01) CD4 ∆CD4 ∆ From BLFrom BL Pappa K, et al. ICAAC 2014. Abstract H-647a. SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Treatment-Naive Pts at Wk 144 PatientsWithHIV-1RNA<50c/mL,% DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) 100 90 80 70 60 50 40 30 20 10 0
- 23. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? AE in > 5% of Pts in Either Arm, % DTG + ABC/3TC QD (n = 414) Wk 96 ∆ Wk 144 EFV/TDF/FTC QD (n = 419) Wk 96 ∆ Wk144 Any 44 +1 67 +1.2 Dizziness 7 +0 33 +0.2 Abnormal dreams 7 +0 16 +0.2 Nausea 11 +0.2 12 +0 Insomnia 10 +0 6 +0.7 Diarrhea 6 +0 8 +0 Fatigue 7 +0 7 +0 Headache 6 +0 7 +0 Rash < 1 +0 8 +0 Pappa K, et al. ICAAC 2014. Abstract H-647a. SINGLE: Common Adverse Events at Wk 144 Overall low rate of elevated liver chemistries in both treatment groups AEs leading to d/c occurred in 4% (DTG) vs 14% (EFV)
- 24. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? SPRING-2: DTG + NRTIs vs RAL + NRTIs in Treatment-Naive Pts Randomized, double-blind, noninferiority phase III study Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 ART-naive pts, HIV-1 RNA ≥ 1000 copies/mL (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. Raffi F, et al. Lancet. 2013;381:735-743.
- 25. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? SPRING-2: DTG vs RAL + 2 NRTIs in Treatment-Naive Pts at Wk 96 Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. DTG + 2 NRTIs (n = 411) RAL + 2 NRTIs (n = 411) 81% 76% 100 80 60 40 20 0 Baseline Wk 4 8 16 24 32 48 60 72 968440120 88% 85%
- 26. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? SPRING-2: Change in Creatinine Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 40 30 20 10 0 -20 -10 Wk 4 8 16 24 32 48 60 72 968440120 DTG + 2 NRTIs (n = 411) RAL + 2 NRTIs (n = 411) Dolutegravir n = Raltegravir n = 401 403 397 400 393 391 389 388 390 387 384 375 371 354 374 354 364 355 358 348 351 338 342 327
- 27. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? FLAMINGO: DTG + NRTIs vs DRV/RTV + NRTIs in Treatment-Naive Pts Randomized, open-label, noninferiority phase III study Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) ART-naive pts, HIV-1 RNA ≥ 1000 c/mL, no PI or NRTI resistance (N = 484) Clotet B, et al. Lancet. 2014;383:2222-2231.
- 28. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Treatment-Naive Pts at Wk 48 Clotet B, et al. Lancet. 2014;383:2222-2231. DTG + 2 NRTIs (n = 242) DRV/RTV + 2 NRTIs (n = 242) 90% 83% 100 80 60 40 20 0 Baseline Wk Adjusted difference at Wk 48: 7.1% (95% CI: 0.9-13.2; P = .025) 4 8 12 16 24 36 480
- 29. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? FLAMINGO: Common Adverse Events AE, % DTG + 2 NRTIs (n = 242) DRV/RTV + 2 NRTIs (n = 242) D/c due to AE or death 1 4 Any event, ≥ 5% in either arm 85 85 Diarrhea 17 29 Nausea 16 18 Headache 15 10 Nasopharyngitis 9 8 Upper respiratory tract infection 5 10 Insomnia 7 6 Cough 5 7 Vomiting 6 6 Fatigue 6 5 Pyrexia 5 6 Dizziness 6 5 Rash 4 6 Back pain/arthralgia 4/2 5/5 Pharyngitis/bronchitis/sinusitis 3/2/2 5/5/5 Depression 5 2 Clotet B, et al. Lancet. 2014;383:2222-2231.
- 30. Use in Clinical Practice
- 31. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Integrase Inhibitor Options for First-line Antiretroviral Therapy Drug Dosing STR Boosting Required Any Resistance in Pts With Failure Cross- Resistance Raltegravir Twice daily No No Yes Yes Elvitegravir Once daily Yes Yes Yes Yes Dolutegravir Once daily Yes No None so far Partial
- 32. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Major Primary INSTI Resistance Mutations HSA G HRK NQ G S Q E IAK T Adapted from the Stanford HIV Drug Resistance Database. H N RCH Y KA E HRK Q Q E SA HRK Q Q E G E KA T A E KA G SA R K Mutations in ORANGE associated with highest levels of reduced susceptibility or response. Mutations in YELLOW reduce INSTI susceptibility or response. 15597 14814792 155140 1481479266 138Elvitegravir 155143140 14892 13866Raltegravir 263140 14813892Dolutegravir
- 33. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Selected Drug–Drug Interactions of INSTIs Agent Potential Drug-Drug Interactions Raltegravir[1] Metabolized by UGT1A ATV increases RAL concentrations; dose adjustment not recommended Avoid aluminum- and/or magnesium-containing antacids Rifampin decreases RAL levels; double RAL dose if coadministered with rifampin Elvitegravir/ cobicistat[2] Metabolized by CYP3A, CYP2D6 COBI increases levels of drugs metabolized by CYP3A Separate dosing with aluminum- and/or magnesium-containing antacids Not recommended for use with rifamycins Dolutegravir[3] Metabolized by UGT1A, with contribution from CYP3A Avoid use with ETR unless coadministered with boosted PI; avoid dosing with NVP Separate dosing with aluminum- and/or magnesium-containing antacids DTG may increase metformin concentrations; metformin dose adjustment may be needed; monitor clinically when starting or stopping DTG 1. Raltegravir [package insert]. 2. EVG/COBI/TDF/FTC [package insert]. 3. Dolutegravir [package insert].
- 34. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Current DHHS and IAS-USA Guidelines: Recommended INSTIs for First-line ART RAL + TDF/FTC EVG/COBI/TDF/FTC – Only for pts with pretreatment CrCl ≥ 70 mL/min[1,2] DTG + TDF/FTC DTG + ABC/3TC* – Only for pts who are HLA-B*5701 negative[1,2] 1. DHHS Guidelines. May 2014. 2. Günthard H, et al. JAMA. 2014;312:410-425. *Guidelines predate availability of single-tablet regimen.
- 36. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Recent and Anticipated Developments in the INSTI Field DTG/ABC/3TC single-tablet regimen EVG/COBI/TAF/FTC single-tablet regimen DTG/RPV single-tablet regimen RAL/3TC once-daily coformulation Cabotegravir (S/GSK1265744)
- 37. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary INSTI-based regimens have demonstrated at least noninferior efficacy vs regimens containing boosted PIs or NNRTIs in treatment-naive pts – INSTIs generally well tolerated – Some INSTIs have low resistance barrier (RAL, EVG) – No emergent resistance to date with first-line DTG failure INSTI-based regimens are among preferred options for first-line ART Once-daily INSTI-based STRs are available (EVG, DTG) – More anticipated in future
- 38. Joseph J. Eron, Jr., MD Professor of Medicine and Epidemiology University of North Carolina School of Medicine Director, AIDS Clinical Trials Unit University of North Carolina Chapel Hill, North Carolina Panel Discussion: Are Integrase Inhibitors the New Gold Standard for First-line Antiretroviral Therapy?
- 39. Panel Discussion
- 40. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Key Questions for Debate When selecting a first-line regimen, should INSTI-based options be the “default” choice? For which pts, if any, might there not be an appropriate first-line INSTI-based regimen? In the absence of head-to-head first-line trials, what considerations related to efficacy and safety should influence the choice between available INSTI-based regimens? How do considerations such as availability of coformulations, dosing frequency, drug–drug interactions, and so on, affect the decision-making process for individual pts?
- 41. Case 1: A 24-Yr-Old Male Recently Diagnosed HIV Positive
- 42. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Case 1: 24-Yr-Old Male Recently Diagnosed HIV Positive 24-yr-old black MSM recently diagnosed HIV positive HIV-1 RNA: 187,000 c/mL; CD4+ count: 448 cells/mm3 HIV genotype: WT, HBV immune, HCV Ab negative; CrCl: 120 mL/min; AST/ALT normal; HLA-B*5701 negative No significant past medical history, no medications, occasional alcohol and marijuana use, sexually active with 1 steady HIV-negative partner Has attended several clinic visits and is interested in starting HIV therapy; prefers to take as few pills as possible but wants what you think is best
- 43. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Many options are available for initial therapy Most pts opt for a single-tablet regimen over a multitablet regimen, given the choice – Simpler dosing, fewer copays A variety of single-tablet regimens would be appropriate choices for the case pt – He is young and healthy and has no comedications or comorbidities
- 44. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Efavirenz/TDF/FTC: extensive clinical experience with this agent, but CNS adverse events may persist Rilpivirine/TDF/FTC: not recommended for this pt due to HIV-1 RNA > 100,000 copies/mL Dolutegravir/ABC/3TC: data are supportive of this option, including in pts with high HIV-1 RNA Elvitegravir/COBI/TDF/FTC: also a popular choice as it is well tolerated and trials have demonstrated noninferior efficacy vs PI-based or NNRTI-based therapy
- 45. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Panel Discussion What if the pt were a woman with HIV-1 RNA 87,000 c/mL who is considering pregnancy in the near future – Would this change your approach? 24-yr-old black woman recently diagnosed HIV positive HIV-1 RNA: 87,000 c/mL; CD4+ count: 448 cells/mm3 HIV GT: WT, HBV immune, HCV Ab-; CrCl: 120 mL/min; AST/ALT normal; HLA-B*5701- No comedications, occasional alcohol/marijuana use, steady HIV-negative partner Starting HIV therapy, prefers few pills as possible
- 46. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Important to discuss risk and assess the pt’s knowledge and plans Most data on ART in pregnancy concerns boosted PIs, particularly ATV/RTV, LPV/RTV – Most NRTI data with ZDV/3TC, increasingly with TDF/FTC Panel believed most women choose not to take an STR when presented with these data Panel would not choose an EFV-based regimen for a woman planning pregnancy; however, therapy should not be switched if a woman receiving EFV-based therapy becomes pregnant Other STRs could be considered for this pt, although data on their use in pregnancy are lacking Data from women receiving ART in pregnancy should be added to the Antiretroviral Pregnancy Registry (www.apregistry.com)
- 47. Case 2: A 28-Yr-Old Male With Advanced HIV Infection
- 48. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Case 2: 28-Yr-Old Male With Advanced HIV Infection 28-yr-old HIV-infected MSM, previously refused ART, now referred to you for specialist care HIV-1 RNA: 78,300 c/mL; CD4+ count: 70 cells/mm3 HIV GT: WT RT/pro; HBV Ag+; HBV DNA: 34 million IU/mL, HCV neg; ALT: 78 IU/L; Cr: 0.8 mg/dL (70.7 µmol/L); CBC: normal Physical exam reveals woody edema of right leg with some discoloration at the ankle, no palpable adenopathy; subsequent biopsy shows KS Binges on alcohol; denies other drug use or sexual activity He will try ART if you recommend it
- 49. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Nonadherence is a concern in this pt Some panelists would choose a boosted PI due to low risk of resistance at failure DTG + TDF/FTC may be another option, as it is well tolerated and convenient, and available data suggest risk of resistance at failure is also very low RAL-based therapy may be a good choice for coadministration with chemotherapy due to lack of drug– drug interactions RPV-based therapy is not recommended for this pt due to CD4+ cell count < 200 cells/mm3
- 50. Use of Integrase Inhibitors in Primary NNRTI Resistance
- 51. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Case 3: 68-Yr-Old Female With Primary NNRTI Resistance 68-yr-old black woman recently diagnosed HIV positive Ready to begin ART following several clinic visits HIV-1 RNA: 215,600 c/mL; CD4+ count: 350 cells/mm3 Believes she acquired HIV from her husband who died 8 or 9 yrs ago HTN well controlled on diuretic; UA: 1+ protein; CrCl: 50 mL/min; US shows slightly enlarged kidneys with no obstruction; nonsmoker, no alcohol use Anti-HBs positive; HCV Ab negative; ALT: 37 IU/L, HLA-B*5701 negative HIV RT/pro genotype detects K103N, no other mutations
- 52. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion The pt likely acquired HIV from her husband at least 8 or 9 yrs ago; therefore, integrase resistance is unlikely Most panelists do not routinely order integrase genotypes – May be more likely to do so in recently infected pts, particularly those with transmitted resistance A combined genotype test is available that assesses RT, protease, and integrase genes
- 53. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Renal biopsy may be considered to assess whether the pt’s renal dysfunction is related to HIV infection ABC/3TC or daily TDF/FTC may be reasonable options with careful monitoring – ABC/3TC may be less active if M184V is present as a minority species that was not detected on genotyping Panelists would not choose ZDV/3TC or a regimen that did not include 2 NRTIs
- 54. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Rilpivirine is not recommended due to HIV-1 RNA > 100,000 copies/mL Atazanavir/ritonavir is associated with renal dysfunction and may not be the best choice for this pt Darunavir/ritonavir could be used, but simpler regimens are available Elvitegravir/cobicistat is not recommended for pts with creatinine clearance < 70 mL/min Dolutegravir or raltegravir are both options for this pt
- 55. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Efficacy of EVG/COBI/TDF/FTC in Pts With Primary NNRTI Resistance White KL, et al. Resistance Workshop 2012. Abstract 4. Baseline Primary NNRTI Mutation Pts, n (%) Pts With HIV-1 RNA < 50 c/mL at Wk 48 Resistance Analysis Any primary NNRTI mutation 96 (13.7) 83 (86.5) 5 analyzed; no resistance K103N 27 (3.7) 24 (89) 2 analyzed; no resistance V90I 14 (2.0) 11 (79) None analyzed A98G 3 (0.6) 3 (100) NR V106A/I/M 17 (2.4) 17 (100) NR V108I 3 (0.4) 2 (67) 1 analyzed; no resistance E138A 12 (1.7) 11 (92) None analyzed V179D/F/T 19 (2.7) 15 (79) 1 analyzed; no resistance Y181C/I/V 4 (0.6) 3 (75) None analyzed Y188C/H/L 2 (0.3) 2 (100) NR G190A/S 2 (0.3) 1 (50) 1 analyzed; no resistance P225H 2 (0.3) 2 (100) NR
- 56. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Dolutegravir/ABC/3TC is available as a fixed-dose combination and was a popular choice for this pt – However, data on the activity of dolutegravir-based therapy in pts with primary NNRTI resistance are lacking Data on the use of darunavir/ritonavir with ABC/3TC are limited Rilpivirine and atazanavir/ritonavir remain unsuitable Raltegravir has been studied with ABC/3TC and may be considered in this pt
- 57. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even for High BL VL In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA* Eron J, et al. Glasgow 2012. Abstract P204. < 100k 100K - < 250K 250K - 500K > 500K 0 20 40 60 80 100 HIV-1RNA<50c/mLatWk48by FDASnapshotAnalysis(%) 86 n/ N = 88 225/ 257 91 306/ 335 36/ 42 82 72/ 88 81 13/ 16 76 29/ 38 72 13/ 18 64 18/ 28 Baseline HIV-1 RNA (c/mL) TDF/FTC ABC/3TC *Pooled data from both INSTIs.
- 58. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Panel Discussion What if the pt had CVD and renal disease? – Modification: DM on metformin, PTCA with stent for an RCA lesion 2 yrs ago, no chest pain on β-blocker and atorvastatin, CrCl: 30 mL/min with 3+ microalbuminuria Would you use a regimen sparing 2 NRTIs? If so, which one? 68-yr-old female recently diagnosed HIV positive HIV-1 RNA: 215,600 c/mL; CD4+ count: 350 cells/mm3 HTN controlled on therapy, DM on metformin, PTCA with stent, β-blocker and atorvastatin, CrCl: 30 mL/min Anti-HBs+; HCV Ab-; ALT: 37 IU/L; HLA-B*5701- HIV RT/pro genotype: K103N, no integrase resistance
- 59. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Some panelists would still consider a regimen containing 2 NRTIs for this pt, though perhaps utilizing tenofovir/FTC dosed every other day NRTI-sparing or NRTI-limiting regimens could be another option
- 60. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? D:A:D: Current ABC Use Associated With 98% Increase in Acute MI Risk Current ABC use remained associated with increased acute MI risk in updated post-2008 analysis – Similar RR in post-2008 group vs pre- 2008 group, despite decrease in ABC use in pts with high CVD risk – Absolute risk in post-2008 group small: 6 cases/2000 PY vs 3 cases/ 2000 PY or absolute risk ↑ 0.15% Overall cohort: 941 MI events during 367,599 PYs – 0.47/100 PYs (95% CI: 0.42-0.52) with current ABC – 0.20/100 PYs (95% CI: 0.19-0.22) with no current ABC No Current ABC Events/PYs 600/295,642 425/169,417 175/126,225 Rate/100 PYs 0.20 (0.19-0.22) 0.25 (0.23-0.28) 0.14 (0.12-0.16) Current ABC Events/PYs 341/71917 247/40833 94/31084 Rate/100 PYs 0.47 (0.42-0.52) 0.61 (0.53-0.68) 0.30 (0.24-0.36) Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission. 5 4 3 2 1 0.7 Overall Pre-3/08 Post-3/08 Adjusted Relative Rate of MI in Pts Currently Receiving ABC 1.98 (1.72-2.29) 1.97 (1.68-2.33) 1.97 (1.43-2.72)
- 61. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? FDA Meta-analysis of Risk of Myocardial Infarction in ABC Trials FDA trial-level meta-analysis of 26 completed RCTs of ABC in adults, with N > 50 subjects Studies MI Events/Subjects Risk Difference, % (95% CI) Odds Ratio (95% CI)ABC Non-ABC Manufacturer trials 6/2341 9/2367 -0.11 (-0.43 to 0.21) 0.70 (0.25-2.00) ACTG trials 12/1985 9/1610 0.03 (-0.45 to 0.51) 1.06 (0.43-2.61) Other* 6/702 4/863 0.31 (-0.53 to 1.16) 1.60 (0.46-5.62) Overall 24/5028 22/4840 0.008 (-0.26 to 0.27) 1.02 (0.56-1.84) Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447. *Other non-ACTG academic sources.
- 62. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Darunavir/RTV plus raltegravir was noninferior to darunavir/RTV plus TDF/FTC in NEAT – NRTI-sparing regimen appeared less efficacious at high HIV-1 RNA, although the difference between regimens was not statistically significant Darunavir/RTV plus maraviroc was inferior to darunavir/RTV plus TDF/FTC in MODERN Lopinavir/RTV plus raltegravir was comparable to lopinavir/RTV plus TDF/FTC in PROGRESS; although this was a small study Lopinavir/RTV plus 3TC was comparable to lopinavir/RTV plus 2 NRTIs in GARDEL, including in pts with high HIV-1 RNA Most panelists opted for darunavir/RTV plus dolutegravir plus 3TC; although this is an untested regimen
- 63. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? NEAT: RAL + DRV/RTV Noninferior to TDF/FTC + DRV/RTV in Naive Pts at 96 Wks Randomized, open-label phase III study of DRV/RTV + RAL vs DRV/RTV + TDF/FTC in ART-naive pts Raffi F, et al. Lancet. 2014;[Epub ahead of print]. Overall N = 805 BL HIV-1 RNA < 100,000 c/mL ≥ 100,000 c/mL n = 530 n = 275 BL CD4+ cell count < 200/mm3 ≥ 200/mm3 n = 123 n = 682 Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL - TDF/FTC RAL TDF/FTC Adjusted Diff. (95% CI) 17.8 13.8 4.0 (-0.8 to 8.8) 7.4 36.8 7.3 27.3 0.1 (-3.8 to 4.0) 9.6 (-0.1 to 20.1) 43.2 13.7 20.9 12.3 22.3 (7.4 to 37.1) 1.4 (-3.5 to 6.3) -10 0 10 20 4030
- 64. Use of Integrase Inhibitors in HIV/HCV Coinfection
- 65. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Case 4: 45-Yr-Old Male With HIV/HCV Coinfection 45-yr-old white man referred to hepatology for low platelet count (74,000/mL); ALT: 45 IU/L; AST: 101 IU/L; and a brief episode of hematemesis HCV GT1a; HCV RNA: 1.2 million IU/mL HIV-1 RNA: 13,000 c/mL; CD4+ count: 450 cells/mm3 ; HIV genotype WT; Cr: 2.5 mg/dL (221 µmol/L); HLA-B*5701 negative EGD: small nonbleeding varices; TE: 17 kPa, no liver biopsy; US: likely cirrhosis, no masses; AFP: 5.6 μg/L He is referred to you for ART consultation before beginning HCV therapy with sofosbuvir + simeprevir
- 66. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion There was no consensus among panelists about the best approach for this pt – HIV therapy could be deferred until HCV therapy is completed, given the relatively short duration of the latter – HCV therapy could be initiated soon after initiation of HIV therapy, once the pt is tolerating ART Panelists would not defer HIV therapy in pts with low CD4+ cell counts
- 67. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary of Panel Discussion Efavirenz, atazanavir/ritonavir, and darunavir/ritonavir should not be coadministered with simeprevir Rilpivirine is an option for this pt, although this agent is more commonly used with TDF/FTC than with ABC/3TC Most panelists opted for dolutegravir or raltegravir – Raltegravir can be administered with simeprevir; requires twice-daily dosing but switch to simpler HIV therapy may be possible following completion of HCV therapy – Dolutegravir can be administered with ABC/3TC as a fixed- dose combination, although estimated CrCl would require close monitoring in this pt to assess 3TC dosing
- 68. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Drug–Drug Interactions With ARVs ARV Simeprevir Sofosbuvir EFV Do not coadminister Use standard doses DRV/RTV Do not coadminister Use standard doses COBI Do not coadminister Use standard doses DLV, ETR, NVP Do not coadminister Use standard doses RTV Do not coadminister Use standard doses Any PI Do not coadminister -- RAL Use standard doses Use standard doses RPV Use standard doses Use standard doses TDF, FTC, ABC, 3TC Use standard doses Use standard doses TPV/RTV Do not coadminister Do not coadminister DTG No data; interactions unlikely No data; interactions unlikely Sofosbuvir [package insert]. Simeprevir [package insert]. Kirby B, et al. AASLD 2012. Abstract 1877. Ouwerkerk-Mahadevan S, et al. IDSA 2012. Abstract 49. http://www.hep-druginteractions.org/
- 69. clinicaloptions.com/hiv Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Summary When selecting a first-line regimen, each of the INSTI- based options can be considered For most pts, at least 1 INSTI-based regimen is likely to be an option Issues such as single-tablet options, choice of NRTI backbone, drug–drug interactions, tolerability, and once- vs twice-daily dosing should influence choice between available INSTI-based regimens
- 70. Go Online for More CCO Coverage of INSTI-Based Therapy ClinicalThought™ commentaries by expert faculty focusing on the practical application of new data, guidelines and regulatory developments Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating the use of integrase inhibitors across the treatment spectrum by expert faculty John J. Eron, Jr., MD and Daniel R. Kuritzkes, MD clinicaloptions.com/firstchoice
Notas do Editor
- Joseph J. Eron, Jr., MD: Thank you for joining us for this very important educational program on the use of integrase inhibitor based regimens in first-line antiretroviral therapy entitled &quot;Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy?&quot; This is an expert faculty debate of the evidence. This presentation and discussion today will be led by myself, Joe Eron, and my colleague, Daniel Kuritzkes. We will be summarizing a discussion of a symposium at the 2014 ICAAC meeting that was held in Washington, DC.
- Joseph J. Eron, Jr., MD: I&apos;m the program director; I&apos;m professor of medicine and epidemiology at the University of North Carolina.
- Joseph J. Eron, Jr., MD: Our faculty for the meeting included Eric Daar, Sally Hodder, Daniel Kuritzkes, and Kathleen Squires. Their affiliations are shown on this slide. During the presentation, I will be summarizing a panel discussion which took place at the symposium.
- Joseph J. Eron, Jr., MD: So now I just want to introduce you to the use of integrase inhibitor based regimens in first-line therapy.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS, International Antiviral Society; INSTI, integrase inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load. Joseph J. Eron, Jr., MD: The DHHS 2014 recommended first-line ART regimens – includes many of the regimens that we&apos;ve seen before, but I&apos;d just like to point out that we now have four integrase inhibitor based regimens as preferred first-line therapy with the only caveat, of course, is when you use abacavir 3TC with dolutegravir. We should make sure that the patients are HLA-B5701 negative. Before I summarize the panel discussion from the symposium, I will turn the program over to Dr. Daniel Kuritzkes, who will lay the foundation by providing a comprehensive overview of data evaluating the safety and efficacy of integrase inhibitors. Thank you.
- Daniel R. Kuritzkes, MD: Hello, I’m Daniel Kuritzkes, Chief of the Division of Infectious Diseases at Brigham and Women’s Hospital, and Professor of Medicine at Harvard Medical School in Boston, Massachusetts. I’ll be speaking about current evidence on integrase inhibitors as first-line therapy for HIV infection. In this talk, I will summarize the key clinical trials data on integrase strand transfer inhibitor-based regimens.
- Daniel R. Kuritzkes, MD: Let’s start by talking about raltegravir, the first of the integrase strand transfer inhibitors, or INSTIs, to be approved for clinical use.
- EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. Daniel R. Kuritzkes, MD: This slide shows the 5-year final data on the STARTMRK study, the original phase III licensing study for raltegravir. This was a randomized, double-blind trial that compared raltegravir to efavirenz, both drugs given with tenofovir and emtricitabine. At the time of the primary endpoint at week 48, raltegravir was shown to be noninferior to efavirenz, but over time differences emerged, and in the final analysis, raltegravir was shown, in fact, to be superior to efavirenz, albeit as a secondary endpoint. We also see that throughout the course of the study, there was a significantly greater increase in CD4 cell count in the raltegravir-treated group as compared to the efavirenz-treated group, a difference that’s been noted in several other studies comparing efavirenz to other therapies. The clinical significance of this difference is yet to be determined.
- ATV, atazanavir; BID, twice daily; CV, cardiovascular; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; QD, once daily; TDF, tenofovir; TF, tolerability failure; VF, virologic failure. Daniel R. Kuritzkes, MD: More recently, raltegravir has been compared to two boosted protease inhibitors in the AIDS Clinical Trials Group study A5257. This was a randomized, open-label, phase III trial with two primary endpoints. The time to virologic failure and the time to discontinuation of the randomized component of the regimen, the raltegravir or the boosted PI, for reasons of toxicity. In addition, the study had a secondary composite endpoint which combined the virologic failure endpoint and the tolerability endpoint. The study was conducted in treatment-naïve patients and enrolled 1,800 patients and was powered as an equivalent study to compare each of the regimens in three 2-way comparisons.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: This slide shows the primary virologic failure endpoint, and you can see that for the three pair-wise comparisons each of the regimens is statistically equivalent to the other; so raltegravir, and the two boosted protease inhibitors each performed equally well.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: Some differences emerge when we look at the tolerability endpoint. Here we see that raltegravir was clearly superior to boosted atazanavir, and boosted darunavir was superior to boosted atazanavir as well. However, from a tolerability perspective, raltegravir and boosted darunavir come out being equivalent.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: If we combine the tolerability and virologic failure endpoints, we see that there is some greater separation in the regimens. Now, considering both endpoints together, the raltegravir continues to be superior to boosted atazanavir, but also comes out superior to boosted darunavir. And boosted darunavir is still superior to boosted atazanavir, considering virologic failure and tolerability.
- ATV, atazanavir; d/c, discontinuation; DRV, darunavir; LFT, liver function test; RAL, raltegravir; RTV, ritonavir. Daniel R. Kuritzkes, MD: This next slide examines the reasons for tolerability failure, and you can see that there were GI toxicities in both the boosted atazanavir and boosted darunavir arms, whereas there was relatively little toxicity in the raltegravir arm. There was also, as expected, a fair bit of jaundice and hyperbilirubinemia in the boosted atazanavir arm. It should be noted that in this study, the discontinuations for jaundice were driven primarily by patient request. There’s a lot more discontinuation for jaundice in this study than in many other studies that have been reported with boosted atazanavir, and the way in which the study was conducted may account for that. Specifically, patients who decided that they wanted to stop a study drug were offered an alternative drug and allowed to continue in the study, so there was little penalty for stopping study-assigned treatment. By contrast, in many other studies, once the patient discontinues the randomized assigned treatment, they are removed from study, and so there may be greater willingness to tolerate higher levels of jaundice in order to stay in a study.
- Daniel R. Kuritzkes, MD: Let’s turn now to elvitegravir.
- ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: There were two phase III trials conducted of elvitegravir that contributed to the approval of this drug, Study 102 and 103. Both were randomized, double-blind, phase III trials with the primary endpoint being viral suppression at week 48. In Study 102, the fixed-dose combination of elvitegravir together with the boosting agent cobicistat and tenofovir and emtricitabine was compared to the fixed-dose combination of efavirenz with tenofovir and emtricitabine, and in Study 103, the same four-drug elvitegravir fixed-dose combination was compared to boosted atazanavir plus the fixed-dose combination of tenofovir and emtricitabine. The study enrolled treatment-naïve patients with normal renal function.
- ATV, atazanavir; BL, baseline; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: This slide shows the results of the trials followed out to 144 weeks. If we focus first on the primary endpoint at week 48, we can see that when the elvitegravir regimen was compared to efavirenz in Study 102 or to boosted atazanavir in Study 103, in both cases elvitegravir was noninferior to efavirenz, meeting the goal of the study. Noninferiority continued to be met at weeks 96 and 144 into the comparisons with each of the study regimens.
- ATV, atazanavir; CNS, central nervous system; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; RTV, ritonavir. Daniel R. Kuritzkes, MD: If we look at the adverse events in these studies, not surprisingly in Study 102 there were more CNS side effects in the efavirenz arm as well as more rash as compared to the elvitegravir and cobicistat arm, but there was more nausea in the elvitegravir and cobicistat arm compared to efavirenz. And in Study 103 where elvitegravir was compared to the boosted PI, not surprisingly there was more jaundice or scleral icterus observed in the boosted atazanavir arm as compared to the elvitegravir arm. But it’s interesting to note that the gastrointestinal side effects were of similar frequency in the elvitegravir/cobicistat arm as compared to the ritonavir-boosted atazanavir arm. The occurrence of GI side effects with cobicistat may account for why the elvitegravir regimen ended up being noninferior rather than superior to efavirenz, and similarly noninferior rather than superior to the boosted atazanavir arm; given similar virologic efficacy, there’s apparently a trade-off in the types of side effects that are occurring, especially when looking at the efavirenz study, so that at the end of the day the regimens end up being relatively similar in their overall efficacy.
- ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: One important feature about the use of cobicistat is that it inhibits the transport of creatinine by the renal tubule, blocking secretion of creatinine and leading to a modest increase in serum creatinine levels. This is solely due to pharmacologic antagonism of creatinine secretion and has been clearly demonstrated not to reflect any pathology at the level of the renal tubule. However, there is a measurable increase in serum creatinine, as shown on this slide. That creatinine increase occurs promptly after treatment initiation and then stabilizes and remains essentially the same over the course of the study. Similar degrees of creatinine elevation were observed in the two studies with the elvitegravir regimen. It’s notable that there is also an increase in the atazanavir/ritonavir arm because there is also some inhibition of creatinine secretion with ritonavir. And as has emerged from data presented more recently, it is possible that tenofovir may also be contributing to some inhibition of creatinine secretion.
- Daniel R. Kuritzkes, MD: Let’s move now to look at the last of the INSTIs, the most recently approved drug, dolutegravir.
- 3TC, lamivudine; ABC, abacavir; CrCl, creatinine clearance; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Daniel R. Kuritzkes, MD: There are three treatment-naïve studies that we’ll be discussing. The first of these is the SINGLE trial. In this study, dolutegravir together with the fixed-dose combination of abacavir and 3TC was compared to the fixed-dose combination of efavirenz, tenofovir, and FTC in treatment-naïve patients. This was a randomized, double-blind trial and it was designed as a noninferiority study with the now traditional endpoint of viral suppression at week 48.
- 3TC, lamivudine; ABC, abacavir; BL, baseline; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Daniel R. Kuritzkes, MD: At the conference at ICAAC in Washington, Keith Pappa presented the 144-week follow-up of this trial, and on this slide we see the comparison of the two regimens at the primary endpoint, week 48, at week 96, and then the final week 144 data. This study showed for the first time the superiority of an integrase strand transfer inhibitor-based regimen when compared to an efavirenz-based regimen. At the primary endpoint of week 48, 88% of patients in the dolutegravir arm versus 81% of patients in the efavirenz arm had virologic suppression, and dolutegravir was statistically superior to the efavirenz regimen. That difference is sustained throughout the course of the study, and at the end of the study, although there was some loss to follow-up in both arms so that the net suppression is a little lower for both arms, nevertheless, dolutegravir remains superior to efavirenz at week 144. In addition, once again we see a significantly greater increase in CD4 count in the dolutegravir arm as compared to the efavirenz arm, with an approximately 380-cell increase in the dolutegravir arm and about a 330-cell increase in the efavirenz arm.
- 3TC, lamivudine; ABC, abacavir; AE, adverse event; d/c, discontinuation; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Daniel R. Kuritzkes, MD: If we look at the common adverse events in this study over 144 weeks, by the end of the study 14% of patients in the efavirenz arm compared to only 4% of patients in the dolutegravir arm had discontinued randomized treatment due to an adverse event. Overall, about two-thirds of the patients in the efavirenz arm versus about 45% of the patients in the dolutegravir arm had evidence of an adverse event. Not surprisingly, these were most commonly psychiatric events in the efavirenz arm, including dizziness and abnormal dreams, as well as a higher frequency of rash which was very uncommon in the dolutegravir arm. Another important point to note, as highlighted on the slide, is that between week 96 and the end of the study at week 144, there were relatively few additional adverse events that occurred in either arm, suggesting that once patients had gotten over the initial period of treatment, those who were tolerating the regimen and remained on their regimen experienced few additional adverse events.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; DTG, dolutegravir; FTC, emtricitabine; QD, once daily; RAL, raltegravir; TDF, tenofovir. Daniel R. Kuritzkes, MD: The second study we’ll talk about is the SPRING-2 trial. This was a randomized comparison of dolutegravir versus raltegravir, a head-to-head study with another integrase inhibitor. In this study, patients were able to choose which nucleoside RT inhibitor combination they took as the background therapy; either tenofovir/FTC, or abacavir/3TC. Once again, this was a randomized, double-blind, noninferiority study with a primary endpoint of viral suppression at week 48.
- DTG, dolutegravir; RAL, raltegravir. Daniel R. Kuritzkes, MD: When we look at the results of this trial, we see that the two regimens were exactly the same in their efficacy at week 48, the primary endpoint; 88% of patients in the dolutegravir arm and 85% of patients in the raltegravir arm had virologic suppression, and that suppression is sustained out to week 96, making dolutegravir noninferior to raltegravir.
- DTG, dolutegravir; RAL, raltegravir. Daniel R. Kuritzkes, MD: Dolutegravir has a modest effect on tubular secretion of creatinine, just as cobicistat does, and in this study we see the increase in serum creatinine occurring during the first four weeks of treatment and then stabilizing thereafter. You’ll note that in the raltegravir arm there’s also a modest but smaller increase, and this may again be due to tenofovir.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir. Daniel R. Kuritzkes, MD: The last study we’ll discuss is the FLAMINGO trial. This was a randomized comparison of dolutegravir to the boosted protease inhibitor darunavir with ritonavir, again in treatment-naïve patients, and once again patients were able to select which of two nucleoside combinations they used as background therapy, either tenofovir/FTC or abacavir/3TC. This was a randomized noninferiority study, but this study was open-label, and the endpoint once again was virologic suppression at week 48.
- DRV, darunavir; DTG, dolutegravir; RTV, ritonavir. Daniel R. Kuritzkes, MD: If we look at the primary data from the study, we see that – as we’ve come to expect with the integrase inhibitor regimen – there was a faster suppression of HIV RNA and more rapid attainment of a fully-suppressed virus load, and then the comparator arm catches up over time, but actually in this study doesn’t catch up all the way. And at the primary endpoint at week 48, 90% of patients in the dolutegravir arm and 83% of patients in the boosted darunavir arm were virologically suppressed, which was a statistically significant difference so that dolutegravir was, in fact, superior to boosted darunavir.
- AE, adverse event; D/c, discontinuation; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; RTV, ritonavir. Daniel R. Kuritzkes, MD: Looking at the common adverse events, I think these data help explain the difference seen in the primary analysis; 4% of patients in the boosted darunavir arm versus only 1% of patients in the dolutegravir arm discontinued the study either due to adverse events or death, and there were more GI side effects, particularly diarrhea, in the boosted darunavir arm compared to the dolutegravir arm. There was slightly more headache in the dolutegravir arm, but that is not very significant, and otherwise the adverse events overall are quite similar in the two arms.
- Daniel R. Kuritzkes, MD: Let’s talk now about the use of these drugs in clinical practice.
- STR, single-tablet regimen. Daniel R. Kuritzkes, MD: If we line the three drugs up and compare them according to a variety of parameters, we can see that both elvitegravir and dolutegravir can be dosed once daily, but raltegravir needs to be dosed twice daily. Likewise, both elvitegravir and dolutegravir are available as single tablet regimens, but raltegravir currently is not. On the other hand, if we ask whether boosting is required, that is the case with elvitegravir which is only available for treatment-naïve patients in a co-formulation with the booster cobicistat, whereas raltegravir and dolutegravir do not require boosting. Both raltegravir and elvitegravir may be associated with emergence of resistance at the time of virologic failure, but to date in treatment-naïve patients who have been treated with dolutegravir and then experienced virologic failure, we have not observed any resistance to dolutegravir. That may change as more data accumulate, but thus far there really is no report of resistance at the time of failure in first-line therapy with dolutegravir. Also, there is extensive cross-resistance between raltegravir and elvitegravir, whereas resistance to those two drugs produces only partial cross-resistance to dolutegravir.
- Daniel R. Kuritzkes, MD: The issue of resistance is discussed more extensively on this slide. You can see with the pattern of mutations that there are great similarities in the number and type of mutations associated with resistance to raltegravir and elvitegravir, and a much more limited set that are involved with dolutegravir. The mutations coded in orange are those that produce the highest levels of resistance or the greatest decrease in clinical response, the ones coded in yellow have some effect on susceptibility and on treatment response but not as much. And you can see that for dolutegravir, really it’s the 148 mutation that is the key resistance mutation. In treatment-experienced studies with dolutegravir, the presence of the 148 mutation with several other integrase inhibitor resistance mutations was needed in order to see a reduction in susceptibility and a reduced response to dolutegravir. Also in treatment-experienced patients, in just two patients a novel mutation at position 263 has been reported, but that mutation has not been seen so far in treatment-naïve patients failing on dolutegravir.
- ATV, atazanavir; COBI, cobicistat; DTG, dolutegravir; ETR, etravirine; NVP, nevirapine; RAL, raltegravir. Daniel R. Kuritzkes, MD: Let’s turn now to talk about some important drug-drug interactions with this class of agents. Because of the way these drugs work and how they interact with the integrase enzyme, all of the drugs – raltegravir, elvitegravir, and dolutegravir – should not be administered with aluminum- or magnesium-containing antacids because they could interfere with drug function. Raltegravir and dolutegravir are metabolized principally by the UGT1A enzyme, whereas for dolutegravir there’s also a contribution from the CYP3A cytochrome system, but elvitegravir is metabolized principally by the cytochrome system CYP3A and CYP2D6. Atazanavir increases raltegravir concentrations, although not to an extent that requires any dose adjustment, and conversely rifampin decreases raltegravir levels to an extent that it’s recommended that the raltegravir dose be doubled if the patient needs rifampin as, for example, people being treated for tuberculosis. Now because elvitegravir is administered with the pharmacologic boosted cobicistat, not surprisingly cobicistat will have an effect on any other drugs the patient may be taking that are also metabolized by the cytochrome system, especially those metabolized by CYP3A, therefore, it is not recommended that elvitegravir and cobicistat be used with rifamycins because of the well-known interaction between the rifamycins and the cytochrome system. And then finishing up with the drug-drug interactions with dolutegravir, because etravirine is an inducer and because dolutegravir is partly metabolized by CYP3A, the use of dolutegravir with etravirine should be avoided unless a boosted protease inhibitor is also being used. Obviously, this would be not be the scenario for use of dolutegravir in first-line therapy, but would be more important for later lines of therapy. More to the point for first-line therapy is that there is an interaction between dolutegravir and metformin. Dolutegravir can increase metformin concentrations, and so clinical monitoring of the blood glucose response to metformin is indicated when starting or stopping dolutegravir, but no specific dose adjustments have been recommended.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; CrCl, creatinine clearance; DHHS, US Department of Health and Human Services; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; HLA, human leukocyte antigen; IAS, International Antiviral Society; RAL, raltegravir; TDF, tenofovir. If we look at the most recent antiretroviral therapy treatment guidelines from the US Department of Health and Human Services and from the IAS-USA, both guidelines panels recommend all three of the integrase strand transfer inhibitors as appropriate for first-line antiretroviral therapy. raltegravir, is recommended for use together with tenofovir/FTC. Elvitegravir is recommended as the fixed-dose combination of elvitegravir, cobicistat, tenofovir, and FTC in patients with normal renal function. And dolutegravir is recommended for use either with tenofovir/FTC or with abacavir/3TC. These recommendations predated the approval of the fixed-dose combination of dolutegravir with abacavir/3TC. And, of course, when using abacavir, the regimen is recommended only for patients who are negative for HLA-B*5701.
- What can we look forward to in new developments in integrase inhibitor therapy?
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RPV, rilpivirine; TAF, tenofovir alafenamide. We just talked about the recent approval of the fixed-dose combination of dolutegravir, abacavir, and 3TC. It is anticipated that shortly we can expect approval of a new elvitegravir fixed-dose combination in which the different formulation of the tenofovir prodrug is substituted, tenofovir alafenamide taking the place of tenofovir disoproxil fumarate. In addition, there are plans to study a fixed-dose regimen of dolutegravir with rilpivirine and a fixed-dose regimen of raltegravir with 3TC probably with other drugs. And then long-acting versions of integrase inhibitors are also being developed; the novel investigational agent cabotegravir, which used to be known as GSK-744, is in clinical trials and may be useful both in prevention and in maintenance therapy.
- ART, antiretroviral therapy; DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir; STR, single-tablet regimen. So to summarize, integrase strand transfer inhibitor-based regimens have demonstrated at least noninferior efficacy when compared to regimens containing boosted protease inhibitors or non-nucleoside reverse transcriptase inhibitors in treatment-naïve patients. INSTIs are generally well-tolerated. Some, like raltegravir and elvitegravir, have a relatively low resistance barrier and resistance may be seen commonly at the time of treatment failure, but to date no resistance has been observed at the time of treatment failure of the dolutegravir-containing regimens. INSTI-based regimens are among the preferred options for first-line therapy, as recommended by both the DHHS and IAS-USA guidelines panels. And once daily single-tablet regimens are available for elvitegravir and dolutegravir, and additional regimens are anticipated in the future. I hope this presentation has been informative, and thank you for your attention.
- Joseph J. Eron, Jr., MD: So now we&apos;ll move to the panel discussion of our cases.
- We hope the cases will bring up discussion of these key questions. So when selecting a first-line regimen, should integrase inhibitor based options be the &quot;default&quot; choice? The second question for debate – for which patients, if any, might there not be an appropriate first-line integrase inhibitor based regimen? Third question – in the absence of head-to-head first-line trials, what considerations related to efficacy and safety should influence the choice between the available integrase inhibitor based regimens? And the fourth question which we&apos;ll debate – how do considerations such as availability of co-formulations, dose frequency, drug-drug interactions, and so on affect the decision-making process for individual patients?
- So here it goes with our first case.
- Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCl, creatinine clearance; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA, human leukocyte antigen; MSM, man who has sex with men; WT, wild type. Case number 1 is a man recently diagnosed HIV positive. He&apos;s a 24-year-old black man MSM. His HIV RNA is 187,000; his CD4 cell count is 448. His HIV genotype for protease and RT is wild-type. Like many of our young patients he&apos;s HBV immune; he&apos;s HCV antibody negative; he has a normal creatinine clearance of 120 mL/min; AST/ALT are normal; and he&apos;s HLA-B5701 negative. He has no significant past medical history; he&apos;s on no medications; he occasionally uses alcohol and marijuana; he&apos;s sexually active with one steady HIV-negative partner. He&apos;s attended several clinic visits and is interested in starting HIV therapy; he prefers to take as few pills as possible but wants what you think is best.
- And our panel discussion at ICAAC really reflected the fact that there are many choices for therapy. But when we discuss therapy with our patients and we feel that a single tablet regimen is likely to be as good as any multiple tablet regimen, most patients actually opt for a single tablet regimen. For them, it&apos;s simpler; they may have fewer co-pays; there&apos;s less to remember. In general, if a single tablet regimen is an acceptable regimen, patients usually go for that as a choice. And I think most of our panel really reflected the same type of thought when discussing this. I think it&apos;s worth noting that this particular patient is young, healthy. He doesn&apos;t have any co-medications; he doesn&apos;t have problems with depression or extensive substance use. So again a single tablet regimen – I&apos;m sure we could find one that would be optimal for this patient.
- 3TC, lamivudine; ABC, abacavir; CNS, central nervous system; COBI, cobicistat; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate. So there&apos;s really a variety of opinions here, which is actually I think fine. The panel discussed many of the options. Efavirenz/tenofovir/FTC has been our standard for a very long time. I think people are appreciating that there are some continued issues with efavirenz based therapy. There are data that we&apos;ve seen that would suggest that some of the CNS related side effects may persist longer than a few weeks or a month. There is a recent publication associating efavirenz with suicidality. The overall risk was actually quite low, though the relative risk was about two-fold. So that&apos;s on people&apos;s minds. Though the panel did say that this is likely to be our least expensive alternative. And again, it is a very solid choice for initial therapy. Rilpivirine/TDF/FTC I think is one that&apos;s probably not correct because of the high viral load. I think that the data from multiple studies suggests that rilpivirine really is best used with a viral load less than 100,000. And in fact, the DHHS guidelines suggest not only less than 100,000 but greater than 200 CD4 cell count. Dolutegravir/abacavir/3TC – Dr. Kuritzkes has gone through the data. It&apos;s a very reasonable initial choice. The data are really strongly supportive of this regimen, even in in high viral load situations. Elvitegravir/COBI/TDF/FTC, also a popular choice, a single tablet with tenofovir/FTC; we&apos;ve actually had a very long experience with tenofovir/FTC in a fixed dose combination with many alternatives. But here with elvitegravir and cobicistat it&apos;s a single tablet; it&apos;s well tolerated, as Dan showed you, and at least as good efficacy as protease inhibitor based therapy or NNRTI based therapy.
- Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCl, creatinine clearance; HBV, hepatitis B virus; HCV, hepatitis C virus; GT, genotype; WT, wild type. So the panel was also given a modification to this case. What if the patient were a woman who is considering pregnancy in the near future? Would this change your approach? So you&apos;ll notice the viral load is a little bit lower, 87,000. And the rest of the data are the same: basically healthy, no hepatitis, normal creatinine clearance, HLA-B5701 negative.
- 3TC, lamivudine; ART, antiretroviral therapy; ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; RTV, ritonavir; STR, single-tablet regimen; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine. Here there are a lot of different opinions. And I think that the predominant one was really discussing, risk and knowledge base with the patient and also what does &quot;near future&quot; mean? Does that mean in the next six month or a year, or does that mean in the next five years? We would have to acknowledge that we have the most data in pregnancy with boosted PI regimens and, in particular, atazanavir/ritonavir or lopinavir/ritonavir, also some data with darunavir/ritonavir. And we have the most data with nucleosides like zidovudine/3TC or now maybe more recently tenofovir/FTC. And I think the panel felt pretty strongly that when you give a woman these options they may well choose not to go with a single tablet regimen. On the other hand, many of the choices are not category D. Efavirenz still remains category D, though, our feeling about efavirenz in pregnancy has changed. I think if we really think a woman is going to start therapy and wants to become pregnant the panel said they wouldn&apos;t choose an efavirenz based regimen. On the other hand, if you have a woman on a efavirenz based regimen and she becomes pregnant, then the guidance now is actually not to switch therapy because basically by the time pregnancy is diagnosed it&apos;s likely that the time of teratogenicity has passed. The panel did say that the other choices – rilpivirine, dolutegravir, and elvitegravir/cobicistat – could be considered in a woman who was considered pregnancy. But the basic thought was that we just don&apos;t have the knowledge base for those drugs yet. And then, Dr. Squires reminded us that if you do have a patient who becomes pregnant it&apos;s very, very important to put the data into the pregnancy registry for antiretrovirals.
- Case 2.
- Ag, antigen; ALT, alanine aminotransferase; ART, antiretroviral therapy; CBC, complete blood count; Cr, creatinine; GT, genotype; HBV, hepatitis B virus; HCV, hepatitis C virus; KS, Kaposi’s sarcoma; MSM, man who has sex with men; RT/pro, reverse transcriptase/protease; WT, wild type. Case 2 is a 28-year-old HIV infected man who has sex with men who previously refused antiretroviral therapy. And he&apos;s now referred to you for specialist care. His HIV RNA is 78,300; his CD4 cell count is 70. His HIV genotype is wild-type for RT and protease; however, he&apos;s HBV antigen positive, and he has a very high HBV DNA level of 34 million. He&apos;s HCV negative; his ALT is slightly abnormal; his creatinine is 0.8; and his CBC is normal. On your physical exam, you find woody edema of the right leg with some discolored lesions at the ankle, though he has no palpable adenopathy. And a subsequent biopsy shows Kaposi’s sarcoma. He admits to you that he binges on alcohol; he denies other drug use or sexual activity. Now that he has a diagnosis of cancer, he will try ART if you recommend it.
- DTG, dolutegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate. So there was a lot of discussion about this case. And really a broad array of choices that people made, though, perhaps the majority were leaning towards darunavir/ritonavir or dolutegravir. I think the discussion of the panel really was here&apos;s an individual who is a potential setup for nonadherence. And Dr. Daar, in particular, I think voiced the sentiment of the panel, which is this is a patient who many of us would choose a boosted protease inhibitor because if the patient doesn’t navigate his or her therapy then the risk of resistance is low. And so, the panel really was leaning towards darunavir/ritonavir. On the other hand, Dr. Kuritzkes said he doesn&apos;t fully understand why when we have a patient who is at risk for adherence we would choose a more complicated regimen. And again, there was some agreement to that point. And I think it&apos;s possible that dolutegravir/tenofovir/FTC, which is very well tolerated therapy – which we saw from the studies, including SPRING-2 and FLAMINGO – may be a regimen that provides a little bit more convenience and tolerability over the boosted PI yet has that same barrier to resistance. But we&apos;re not yet 100% sure. I don&apos;t think any particular therapy here is wrong. One of the panelists&apos; remarked that if the patient has to go on to have chemotherapy maybe a raltegravir based regimen would be best just because that&apos;s one where we&apos;re very comfortable with drug-drug interactions. We were reminded that because of the low CD4 cell count the panel would not choose a rilpivirine based regimen in this setting
- Use of integrase inhibitor based regimens in primary NNRTI resistance.
- Ab, antibody; ALT, alanine aminotransferase; ART, antiretroviral therapy; CrCl, creatinine clearance; HCV, hepatitis C virus; HTN, hypertension; HLA, human leukocyte antigen; RT/pro, reverse transcriptase/protease; UA, urinalysis; US, ultrasound. This is a 68-year-old woman recently diagnosed HIV positive. She&apos;s ready to begin antiretroviral therapy following several clinic visits. Her HIV RNA is high at 215,000; her CD4 is 350. And she believes that perhaps she was infected by her husband who died about eight or nine years ago from an illness that certainly sounded consistent with an AIDS defining illness. Her hypertension is well controlled on a diuretic; her UA shows 1 plus protein with a creatinine clearance of 50 mL/min; ultrasound shows slightly enlarged kidneys with no obstruction; she&apos;s a nonsmoker; she doesn&apos;t use alcohol. And while not stated on this slide, she&apos;s not sexually active and hasn&apos;t been sexually active since her husband died. She&apos;s anti-hepatitis B surface antibody positive so she&apos;s immune to hepatitis B. HCV antibody negative; she has normal ALT; and her HLA-B5701 is negative. However, you do a RT and protease genotype, and you detect a K103N mutation but no other mutations.
- RT, reverse transcriptase. The panel discussed this quite a bit, and I think there were two kind of schools of thought here. The main one, which I think prevailed, was that this woman likely was infected by her husband who died nine years ago. It&apos;s unlikely he would have had integrase inhibitor resistance so there probably isn&apos;t any need in this scenario. Most people we&apos;re not routinely ordering integrase genotypes, though Dr. Squires mentioned that in their clinic it&apos;s become routine because they now have a test, which can get data on both RT protease and integrase in the same test, though that that test typically is more expensive than our old routine RT protease genotype. And people were saying that if they thought that someone was recently infected or if they had transmitted drug resistance and were recently infected those are the kind of folks that they would be getting an integrase genotype.
- 3TC, lamivudine; ABC, abacavir; FTC, emtricitabine; TDF, tenofovir; ZDV, zidovudine. First of all, this may be an individual where you&apos;d actually do a renal biopsy because there&apos;s suggestions here that her renal dysfunction might not be related to her hypertension but instead might be actually related to HIV itself. There&apos;s proteinuria; and in particular, the kidneys are enlarged on ultrasound, which is consistent with HIV-associated nephropathy or HIVAN. So I think the panel really settled that abacavir/3TC or tenofovir/FTC daily might be reasonable with very careful monitoring. I don&apos;t think anybody on the panel felt like zidovudine/3TC would go here because of side effects and twice daily dosing. And I think the panel was uniform in choosing a regimen that included two NRTIs so choice E was not a popular choice. It was mentioned that since she has K103N resistance, and there is a possibility that she has M184V or the 3TC/FTC resistance mutation in the minority, which you can&apos;t detect, that abacavir/3TC might be slightly more vulnerable in that setting.
- Because her viral load was over 100,000, rilpivirine was not considered. And the panel shied way from atazanavir/ritonavir because of the association of atazanavir with renal dysfunction. Darunavir/ritonavir could be chosen, though there were simpler alternatives. And while the panel certainly agreed with the majority that dolutegravir would be appropriate, it would be possible to use choice E, elvitegravir/cobicistat, though the package insert recommends a creatinine clearance greater than 70. There are some data that were presented at the International AIDS meeting on patients with creatinine clearances between 50 and 70. But right now, the package insert would steer you away from elvitegravir/cobicistat. And then finally, raltegravir would certainly be adequate here. And several people mentioned it&apos;s very well tolerated. And depending on what other medications she&apos;s on, she may already be taking twice daily medications.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; NR, not reported; TDF, tenofovir. So there are data on the use of elvitegravir/cobicistat/tenofovir/FTC in patients with primary NNRTI resistance that were presented at the resistance workshop a few years ago, and they&apos;re shown on this slide. In the 103 study, they allowed patients in with NNRTI resistance because elvitegravir in that study was compared with atazanavir/ritonavir so no NNRTI was used. And you can see response rates were very similar to the overall study. We don&apos;t have any data on dolutegravir in patients with NNRTI resistance at least as transmitted drug resistance. And there&apos;s no data – that I&apos;m aware of – with raltegravir. Many people would choose a boosted PI in the setting of transmitted drug resistance. So really there was discussion about darunavir/ritonavir as perhaps being an important choice in this particular setting.
- 3TC, lamivudine; ABC, abacavir. In this case, the majority of responders at ICAAC actually selected dolutegravir, which given its availability in a fixed dose combination I think is a reasonable choice. But again, the panel mentioned that we don&apos;t actually have data on dolutegravir with NNRTI transmitted drug resistance. So the panel still mentioned darunavir/ritonavir, though again, we don&apos;t really have any data on darunavir/ritonavir with abacavir/3TC, except for a small fraction of the patients from the FLAMINGO trial. And then, again, people wouldn&apos;t use rilpivirine; people on the panel shied away from atazanavir/ritonavir. And again, given the data from the SPRING-2 trial on raltegravir with abacavir/3TC, the panel was willing to consider that, but again I think the panel felt most comfortable with dolutegravir if one went with abacavir/3TC.
- 3TC, lamivudine; ABC, abacavir; BL, baseline; DTG, dolutegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir; VL, viral load. These are data from a presentation that I made in Glasgow almost two years ago now looking at outcomes in high viral load patients comparing abacavir/3TC with tenofovir/FTC. The individuals got raltegravir or dolutegravir, in the SPRING-2 trial. And you can see there doesn&apos;t seem to be a lot of difference between the two agents, though you&apos;ll notice with abacavir/3TC the numbers in very high viral load get relatively small. So again, the panel did discuss the fact that in very high viral load and transmitted drug resistance perhaps one would lean towards tenofovir/FTC.
- Ab, antibody; ABC, abacavir; ALT, alanine aminotransferase; ART, antiretroviral therapy; CrCl, creatinine clearance; CVD, cardiovascular disease; DM, diabetes mellitus; HCV, hepatitis C virus; HTN, hypertension; HLA, human leukocyte antigen; PTCA, percutaneous transluminal coronary angioplasty; RCA, right coronary artery; RT/pro, reverse transcriptase/protease; UA, urinalysis; US, ultrasound. The panel also had this modification. What would you do if the patient had substantial evidence of cardiovascular and renal disease? I think Dr. Hodder pointed out that in a older woman with hypertension who has some creatinine clearance abnormalities she probably already has some coronary disease. But in this modification, she has diabetes, which is a coronary risk equivalent. She&apos;s actually already had a stent because she had a known coronary lesion. She doesn&apos;t have any chest pain, no active angina. She&apos;s on a beta blocker and a statin. But now her creatinine clearance is low, 30. And she has microalbuminuria, which is evidence of glomerular injury and not consistent with HIVAN. So the question was would you use a two NRTI sparing regimen? If so, which one?
- FTC, emtricitabine. I can tell you the panel had quite a bit of discussion about this. And while some people were still thinking about using two NRTIs – perhaps even using tenofovir/FTC on an every other day basis – we did get into quite a bit of discussion about so called nuc-sparing or nuc-limiting regimens.
- ABC, abacavir; CVD, cardiovascular disease; MI, myocardial infarction; PY, patient-yrs; RR, relative rate. For more information about this study, go online to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202014/Overview/Capsules/747LB.aspx This is a summary of the D:A:D data. Whether you look at the overall results, the initial results that were presented in 2008, or an update of the results that were presented in 2014 at the CROI meeting basically there&apos;s about a two-fold increase in MI risk in the D:A:D study associated with abacavir use. And while that&apos;s relative risk, obviously if you have a 10% cardiovascular risk and something increases it by two-fold that&apos;s an substantial increase.
- ABC, abacavir; FDA, US Food and Drug Administration; MI, myocardial infarction; RCT, randomized controlled trial. Not everybody is convinced that abacavir is associated with MI risk. This is a FDA analysis of clinical trial data where abacavir was compared in a randomized way to another comparator. And basically they were not able to show any increased risk of MI with abacavir. But again, clinical trials&apos; patients tend not to have high cardiovascular risk, tend not to be older, and are unlikely to have diabetes and renal dysfunction. So again, our panel felt that this woman, as now presented, might be someone where they would consider either nuc-sparing or, nuc-light regimens.
- 3TC, lamivudine; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Probably the most data are available for darunavir/ritonavir plus raltegravir or the so called NEAT study. The panel brought up the fact that the NEAT study those with high viral load seem to be at increased risk for virologic failure. At the Melbourne International AIDS meeting darunavir/ritonavir plus maraviroc was shown to be inferior to darunavir/ritonavir/tenofovir/FTC. So that choice was not popular among the panel. And lopinavir/ritonavir plus raltegravir was investigated in the PROGRESS study, and was shown to be similar to lopinavir/ritonavir plus tenofovir/FTC, but that study was relatively small and also had a very low baseline viral load. The panel discussed the GARDEL study presented and published by Pedro Cahn where lopinavir/ritonavir plus 3TC was as good as lopinavir/ritonavir plus two nucleosides even in high viral load. But I think most of the panel felt that if they were going to choose a nuc-sparing or nuc-light regimen they would go with choice F, a boosted protease inhibitor plus an integrase inhibitor plus 3TC or FTC. If you did darunavir/ritonavir plus dolutegravir and 3TC, you could do it all once a day, though, the caveat was that really has not been tested. So I think this particular patient puts us in uncharted waters.
- BL, baseline; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. Here are the NEAT data. And you can see in the high viral load patients there was a 9.6% difference in outcome with more primary endpoints in the raltegravir/darunavir/ritonavir arm. You can see that did not quite meet superiority of darunavir/ritonavir/tenofovir/FTC. You can note on this slide with low CD4 cell count darunavir/ritonavir/tenofovir/FTC was superior. So again, probably raltegravir/darunavir/ritonavir is an adequate regimen in certain patients, but I think the panel had some trepidation in a person with a viral load of 215,000.
- HCV, hepatitis C virus.
- AFP, alpha-fetoprotein; ALT, alanine aminotransferase; ART, antiretroviral therapy; AST, aspartate aminotransferase; Cr, creatinine; EGD, esophagogastroduodenoscopy; GT, genotype; HCV, hepatitis C virus; HLA, human leukocyte antigen; TE, transient elastography; US, ultrasound; WT, wild type. This is a 45-year-old man referred to hepatology because of a low platelet count, 74,000, and an abnormal AST and who had a brief episode of hematemesis. The hepatologist found that he was infected with both HCV and HIV. His HCV genotype was 1a; he had a high HCV RNA or 1.2 million. His HIV RNA was not that high, 13,000; and his CD4 cell count was 450. And those were similar on repeat. HIV genotype was wild-type; creatinine was 2.5, perhaps related to his hepatitis C, and and this may be someone who also might get a renal biopsy; HLA-B5701 negative. The patient also had a upper endoscopy, an EGD, showing small nonbleeding varices. The patient had a noninvasive elastography test that showed a result of 17 kPa. If you&apos;re not familiar with this test, that result suggests very strongly that the patient has fibrosis. Therefore no liver biopsy was recommended or done. An ultrasound of the right upper quadrant showed likely cirrhosis consistent with the noninvasive test. And there were no masses suggestive of hepatocellular carcinoma. And the alpha fetal protein level was 5.6, which is is not abnormal. He&apos;s referred to you for consultation about antiretroviral therapy because his hepatologist wants to begin sofosbuvir and simeprevir therapy.
- ART, antiretroviral therapy; HCV, hepatitis C virus. Here most people would consider beginning HIV therapy and then start HCV therapy when HIV is suppressed. The panel initially went that way. But there was some discussion that now that HCV therapy is measured in months, and for simeprevir and sofosbuvir likely just three months, though, genotype 1a with cirrhosis is a more difficult to treat group. There was, at least, some consideration about let&apos;s get the hep C cured, and then we&apos;ll move on to HIV therapies, especially given the low viral load and CD4 of 450. Dr. Hodder made the point that you could begin HIV therapy, and you don&apos;t actually have to wait until HIV RNA is suppressed; just wait until you&apos;re sure the patient is tolerating therapy and then begin the HCV therapy. So there was some back and forth about this. Given the high CD4 cell count, there was really not a wrong answer here. Certainly the panel had consensus that if the CD4 was substantially lower that they would begin HIV therapy first.
- 3TC, lamivudine; ABC, abacavir; CrCl, creatinine clearance; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate. Simeprevir has drug-drug interactions with efavirenz, with atazanavir/ritonavir and darunavir/ritonavir and really wouldn&apos;t be recommended. In fact, the panel said that they would not go with those choices because of the need for simeprevir therapy and drug-drug interactions. That leaves us with rilpivirine, dolutegravir, or raltegravir. The panel was split about this. Certainly rilpivirine could be used in this setting, though, we&apos;re most comfortable I think with rilpivirine paired with tenofovir/FTC, though in the ECHO and THRIVE studies patients were allowed to use abacavir/3TC so we have data with rilpivirine/abacavir/3TC. But I think most of the panel were really going along with dolutegravir and raltegravir as their primary choices here. We know there isn&apos;t the drug interaction with raltegravir. It is a twice daily medication, but again one could simplify the therapy once the HCV was treated. And with dolutegravir, of course, would be the opportunity perhaps to have a fixed dose combination, though, one would have to be careful to calculate the estimated creatinine clearance and make sure 3TC dosing was appropriate.
- 3TC, lamivudine; ABC, abacavir; ARV, antiretroviral; COBI, cobicistat; DLV, daclatasvir; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; NVP, nevirapine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate; TPV, tipranavir. So this is just summarizing the drug-drug interactions. And you can see with simeprevir that efavirenz, darunavir/ritonavir, cobicistat, all the other NNRTIs including delavirdine, etravirine, nevirapine are all do not coadminister. Any ritonavir do not coadminister; and PI, basically, do not coadminister. But with raltegravir, rilpivirine, and tenofovir, FTC, abacavir, 3TC the recommendation really is to use standard doses. With dolutegravir, we don&apos;t have any data yet but certainly interactions are unlikely. With sofosbuvir, the right-hand column, really almost everything appears to be fine with the exception of tipranavir/ritonavir.
- When selecting a first-line regimen, I think the panel felt that each of the integrase strand transfer–based options can be considered. In fact, I think in each of our scenarios we did consider them. For most patients at least one of our integrase inhibitor based regimens is likely to be an option. However, issues such as single tablet options, choice of nucleoside backbone, drug-drug interactions, overall tolerability, and once versus twice daily dosing should influence the choice between the integrase strand transfer inhibitors that we have available to us.