Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014, and Glasgow 2014. 2014
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In this downloadable slideset, Joseph J. Eron, Jr., MD and Jürgen K. Rockstroh, MD, review key HIV studies presented at the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow. Format: Microsoft PowerPoint (.ppt) File size: 1.70 MB
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Fall 2014 HIV Update.Clinical Impact of New Data From ICAAC 2014, IDWeek 2014, and Glasgow 2014. 2014
- 1. September 5-9, 2014 Washington, DC Fall 2014 HIV Update CCO Independent Conference Coverage of the 2014 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2014 IDWeek, and 2014 HIV Drug Therapy Glasgow* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an educational grant from This program is supported by an educational grant from Gilead Sciences. October 8-12, 2014 Philadelphia, Pennsylvania November 2-6, 2014 Glasgow, Scotland
- 2. clinicaloptions.com/hiv Fall 2014 HIV Update 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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Fall 2014 HIV Update Faculty 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 Jürgen K. Rockstroh, MD Professor of Medicine Department of Medicine University of Bonn Bonn, Germany
- 4. clinicaloptions.com/hiv Fall 2014 HIV Update Disclosures Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, and Tobira; has served on data and safety monitoring boards for Vertex; and has received funds for research support from GlaxoSmithKline/ViiV. Jürgen K. Rockstroh, MD, has disclosed that he has received consulting fees from AbbVie, Bionor, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen, Merck, Tibotec, Tobira, and ViiV and funds for research support from Gilead Sciences.
- 6. clinicaloptions.com/hiv Fall 2014 HIV Update ATV/COBI + TDF/FTC vs ATV/RTV + TDF/FTC: 144-Wk Report Randomized, double-blinded phase III study Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 – Cobicistat noninferior to ritonavir at Wk 48 by FDA snapshot ITT analysis with HIV-1 RNA < 50 c/mL in 85.2% vs 87.4%[1] ART-naive pts with HIV-1 RNA ≥ 5000 c/mL, any CD4+ cell count, eGFR ≥ 70 mL/min (N = 692) ATV 300 mg QD + COBI 150 mg QD + TDF/FTC 300/200 mg QD (n = 344) Wk 144[2] ATV 300 mg QD + RTV 100 mg QD + TDF/FTC 300/200 mg QD (n = 348) Stratified by screening HIV-1 RNA ≤ vs > 100,000 c/mL 1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. Gallant JE, et al. ICAAC 2014. Abstract H-647. Wk 48: Primary Endpoint[1]
- 7. clinicaloptions.com/hiv Fall 2014 HIV Update ATV/COBI + TDF/FTC vs ATV/RTV + TDF/FTC: Wk 144 FDA Snapshot (ITT) Mean CD4+ cell count increase with cobicistat vs ritonavir: 310 vs 332 cells/mm3 Gallant JE, et al. ICAAC 2014. Abstract H-647. Reproduced with permission. *No data include study drug discontinuation for adverse event/death, study drug discontinuation for other reasons with last available HIV-1 RNA < 50 c/mL, or missing data during window. Virologic Success Virologic Failure 100 80 60 40 20 0 Pts(%) 85 87 78 79 72 74 6 4 7 5 8 5 9 9 15 16 20 21 W48 W96 W144 W48 W96 W144 W48 W96 W144 No Data* COBI (n = 344) RTV (n = 348) 95% Cl for Difference Favors ATV + RTV Favors ATV + COBI -2.2 3.0-7.4 4.7-7.6 -8.7 4.5 -2.1 -1.4 W48 W96 W144 -12% 12%0
- 8. clinicaloptions.com/hiv Fall 2014 HIV Update ATV/COBI + TDF/FTC vs ATV/RTV + TDF/FTC: Serum Creatinine and eGFR Additional renal AEs leading to study drug discontinuation from Wk 96-144 included 1 case of proximal renal tubulopathy in ritonavir arm and 2 cases of isolated Cr increase in COBI arm Gallant JE, et al. ICAAC 2014. Abstract H-647. Reproduced with permission. 0.4 0.3 0.2 0.1 0.0 -0.1 -0.2 20 10 0 -10 -20 -30 -40 BL 24 48 72 96 120 144 -15.1-13.7-12.9 -9.1 -8.3 -7.5 Wk Change in eGFR (mL/min) at Wk 144 COBI: -15 vs RTV: -8 Change in eGFR, Median [IQR] 0.13 Change in Serum Creatinine, Median [IQR] BL 24 48 72 96 120 144 Wk Change in Cr (mg/dL) at Wk 144 COBI: 0.13 vs RTV: 0.07 0.070.080.09 0.13 0.12 COBI RTV mg/dL mL/min
- 9. clinicaloptions.com/hiv Fall 2014 HIV Update No difference in TC:HDL ratio changes between arms Additional treatment-emergent resistance from Wk 96 to Wk 144 in 9 pts in COBI arm vs 7 pts in RTV arm – No cases of primary PI resistance through Wk 144 ATV/COBI + TDF/FTC vs ATV/RTV + TDF/FTC: Lipids and Resistance Gallant JE, et al. ICAAC 2014. Abstract H-647. Reproduced with permission. TC LDL HDL TG P = .35P = .11P = .11P = .4920 15 10 5 0 MedianChangeat Wk144(mg/dL) COBI RTV
- 10. clinicaloptions.com/hiv Fall 2014 HIV Update Dolutegravir Phase III Trials in Treatment- Naive Pts Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 ART-naive pts VL ≥ 1000 c/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. ART-naive pts VL ≥ 1000 c/mL HLA-B*5701 neg CrCl > 50 mL/min (N = 833) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) SPRING-2[1] (active controlled, double blind) SINGLE[2] (active controlled, double blind) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) ART-naive pts VL ≥ 1000 c/mL (N = 484) FLAMINGO[3] (open label) 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Pappa K, et al. ICAAC 2014. Abstract H-647a. 3. Molina JM, et al. Glasgow HIV 2014. Abstract O153.
- 11. clinicaloptions.com/hiv Fall 2014 HIV Update SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC at Both Wk 48 and 144 AE-related study d/c: 4% in DTG vs 14% in EFV arm Resistance through Wk 144: 0 pts with treatment-emergent resistance mutations in DTG arm; 1 pt with NRTI and 6 pts with NNRTI resistance mutations in EFV arm CD4+ count increase at Wk 144 greater with DTG: +379 vs +332 cells/mm3 (P = .003) Separate PK study showed plasma metformin AUC 1.8-fold higher when coadministered with DTG[3] HIV-1RNA<50c/mL(%) 88 81 DTG + ABC/3TC EFV/TDF/FTC 71 63 Wk 48[1] Wk 144[2] 364/ 414 338/ 419 Δ 8.3% (2.0-14.6; P = .01) Δ 7% (2.5-12.3; P = .003) 0 20 40 60 80 100 n/N = 1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Pappa K, et al. ICAAC 2014. Abstract H- 647a. 3. Zong J, et al. Glasgow HIV P052. 296/ 414 265/ 419
- 12. clinicaloptions.com/hiv Fall 2014 HIV Update FLAMINGO: DTG + 2 NRTIs Superior to DRV/RTV + 2 NRTIs at Both Wk 48 and 96 AE-related study d/c: 3% in DTG arm vs 6% in DRV/RTV arm No pts with treatment-emergent resistance mutations in either arm through Wk 96 Mean change in serum creatinine from BL to Wk 96 higher with DTG vs DRV/RTV: 15.35 μmol/L vs 3.93 μmol/L – Caused by known inhibition of tubular creatinine secretion HIV-1RNA<50c/mL(%) 90 83 0 20 40 60 80 100 80 68 Wk 48[1] Wk 96[2] Δ 12.4% (4.7-20.2; P = .002) Δ 7.1% (0.9-13.2; P = .025) n/N = DTG + NRTIs (n = 242) DRV/RTV + NRTIs (n = 242) 1. Clotet B, et al. Lancet. 2014;383:2222-2231. 2. Molina JM, et al. Glasgow HIV 2014. Abstract O153. Reproduced with permission. 217/ 242 200/ 242 NR NR
- 13. clinicaloptions.com/hiv Fall 2014 HIV Update FLAMINGO: Wk 96 Subgroup Efficacy Analysis Molina JM, et al. Glasgow HIV 2014. Abstract O153. Reproduced with permission. HIV-1RNA<50c/mL(%) DTG + NRTIs (n = 242) DRV/RTV + NRTIs (n = 242) 82 75 79 64 52 82 73 80 68 80 100 80 60 40 20 0 TDF/FTC (n = 325) ABC/3TC (n = 159) > 100,000 (n = 122) ≤ 100,000 (n = 362) Overall BL HIV-1 RNA (c/mL) Background NRTI
- 14. clinicaloptions.com/hiv Fall 2014 HIV Update FLAMINGO: Lipid Changes With DTG vs DRV/RTV Through Wk 96 Higher rate of grade ≥ 2 fasting LDL abnormalities by Wk 96 with DRV/RTV vs DTG: 22% vs 7% (P < .001) Molina JM, et al. Glasgow HIV 2014. Abstract O153. Reproduced with permission. DTG + NRTIs (n = 242) DRV/RTV + NRTIs (n = 242) 0.4 0.3 0.2 0.1 0 0.8 0.6 0.4 0.2 0 -0.2 Total Cholesterol LDL Cholesterol Triglyceride s MeanChangeFromBL (mmol/L) MeanChangeFromBL TC:HDL Ratio
- 15. clinicaloptions.com/hiv Fall 2014 HIV Update ENCORE1: EFV 400 vs 600 mg QD + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, noninferiority study Primary endpoint: HIV-1 RNA < 200 c/mL at Wk 96 Carey D, et al. Glasgow HIV 2014. Abstract O421. ART-naive pts with HIV-1 RNA ≥ 1000 c/mL, CD4+ cell count > 50 to < 500 cells/mm3 , CrCl ≥ 50 mL/min (N = 630) EFV 400 mg QD + TDF/FTC 300/200 mg QD (n = 321) Wk 96 EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 309) Stratified by screening HIV-1 RNA ≤ vs > 100,000 c/mL and study site
- 16. clinicaloptions.com/hiv Fall 2014 HIV Update ENCORE1: EFV 400 mg QD Noninferior to 600 mg QD Through 96 Wks Mean change in CD4+ cell count from BL greater with 400-mg vs 600-mg EFV (P = .03) Rate of EFV-related AEs lower with 400-mg vs 600-mg dose: 37.7% vs 47.9% (P = .01) Trend toward lower rate of discontinuation for EFV- related AEs with 400-mg vs 600-mg dose: 8.3% vs 15.5% (P = .07) Frequency of treatment emergent NNRTI resistance similar in both armsCarey D, et al. Glasgow HIV 2014. Abstract O421. Reproduced with permission. 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 0 12 24 36 48 60 72 84 96 321 309 316 302 312 301 310 299 312 295 307 291 304 290 300 289 299 286 Pts at Risk, n EFV 400 mg EFV 600 mg Mean difference: -0.02 log10 c/mL (95% Cl: -0.14 to 0.10; P = .74) ChangeFromBL(HIV-1RNAlog10c/mL) Wk EFV 600 mg QD + TDF/FTC EFV 400 mg QD + TDF/FTC
- 18. clinicaloptions.com/hiv Fall 2014 HIV Update Insurance claims data obtained from commercial insurance database and multistate Medicaid database Suicidality determined by medical coding Primary outcome: suicidality (coded as suicidal ideation or suicide attempt) Secondary outcomes – Suicide attempt (coded as suicide and self-inflicted injury) – Injuries consistent with suicide attempt (coded as poisoning, open wounds, asphyxiation) Adjusted HR for primary outcome of suicidality (vs EFV-free regimens) – Commercial database: 1.03 (95% CI: 0.64-1.67) – Medicaid database: 0.90 (95% CI: 0.62-1.32) Nkhoma E, et al. IDWeek 2014. Abstract 646. Real-World Assessment of Suicidality Risk Among Pts Initiating EFV
- 19. clinicaloptions.com/hiv Fall 2014 HIV Update Real-World Assessment of Suicidality Risk Among Pts Initiating EFV Nkhoma E, et al. IDWeek 2014. Abstract 646. Pt Characteristic Commercial Medicaid EFV (n = 11,187) EFV Free (n = 8796) P Value EFV (n = 2224) EFV Free (n = 2930) P Value Age, yrs (SD) 40.1 (10.4) 40.8 (10.4) < .001 41.7 (11.5) 39.7 (11.6) < .001 Male, % 86.0 79.1 < .001 56.7 50.2 < .001 Any hospitalization, % 15.5 14.1 .007 26.1 24.3 .152 Diabetes, % 5.0 5.0 .905 10.7 9.1 .046 Pain disorders, % 12.5 12.9 .480 22.5 22.4 .960 AIDS-defining illness, % 10.5 8.8 < .001 19.0 18.2 .454 Suicidality, % 0.2 0.4 < .001 1.3 2.9 < .001 Depression, % 16.7 20.0 < .001 29.0 34.8 < .001 Drug dependence, % 0.6 0.9 .017 5.3 8.1 < .001 Anxiety, % 2.3 3.1 < .001 3.8 5.5 .005 Schizophrenia, % 0.04 0.1 .013 3.7 7.0 < .001 On 2nd-gen antipsychotics, % 0.8 1.5 < .001 5.8 9.4 < .001 On antidepressants, % 10.5 12.2 < .001 15.6 16.8 .247
- 21. clinicaloptions.com/hiv Fall 2014 HIV Update PROTEA: Switch to DRV/RTV ± 2 NRTIs for Stably Suppressed Pts on First-line ART Multicenter, randomized, open-label phase IIIb study Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 (ITT; FDA Snapshot) Average duration of initial ARV regimen: 5.5 yrs HIV-infected pts virologically suppressed (HIV-1 RNA < 50 c/mL) on first-line ART; CD4+ nadir > 100 cells/mm3 (N = 273) DRV 800 mg QD + RTV 100 mg QD (n = 137) Wk 48 DRV 800 mg QD + RTV 100 mg QD + 2 NRTIs* (n = 136) Stratified by HCV status *Investigator-selected dual combination of either ABC, 3TC, ZDV, TDF, or FTC. Antinori A, et al. Glasgow HIV 2014. Abstract O423A. Clarke A, et al. Glasgow HIV 2014. Abstract O423B.
- 22. clinicaloptions.com/hiv Fall 2014 HIV Update PROTEA: Virologic Response at Wk 48 No difference in efficacy between treatment arms in “switch included” analysis that classified pts with viral suppression at Wk 48 after reintensification or second switch as virologic responders HIV-1RNA<50c/mL(%) DRV/RTV DRV/RTV + 2 NRTIs 118/ 137 129/ 136 27/ 41 29/ 30 91/ 96 100/ 106 100 80 60 40 20 0 ITT: -8.7% (-1.8% to -15.5%) 86.1 94.9 100 80 60 40 20 0 65.9 96.7 94.8 94.3 Nadir CD4+ Count < 200 cells/mm3 Nadir CD4+ Count ≥ 200 cells/mm3 HIV-1RNA<50c/mL(%) DRV/RTV DRV/RTV + 2 NRTIs DRV/RTV DRV/RTV + 2 NRTIs n/N = n/N = Antinori A, et al. Glasgow HIV 2014. Abstract O423A. Clarke A, et al. Glasgow HIV 2014. Abstract O423B. Reproduced with permission.
- 23. clinicaloptions.com/hiv Fall 2014 HIV Update Antinori A, et al. Glasgow HIV 2014. Abstract O423A. Clarke A, et al. Glasgow HIV 2014. Abstract O423B. Reproduced with permission. PROTEA: Adverse Events Event, n (%) DRV + RTV (n = 137) DRV + RTV + 2 NRTIs (n = 136) Serious AEs 9 (6.6) 5 (3.7) Deaths* 1 (0.7) 0 All AEs 96 (70.1) 83 (61) Grade 3/4 AEs 7 (5.1) 3 (3.7) Psychiatric AEs 10 (7.3) 9 (6.6) Nervous system AEs 13 (9.5) 14 (10.3) *1 pt with myocardial infarction judged to be unrelated to treatment.
- 25. clinicaloptions.com/hiv Fall 2014 HIV Update DRV/COBI/FTC/Tenofovir Alafenamide vs DRV + COBI + FTC/TDF Randomized, double-blind, placebo-controlled phase II study Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 (FDA snapshot, ITT) TAF: novel tenofovir prodrug, yields higher tenofovir diphosphate levels and lower plasma tenofovir levels vs TDF Mills A, ICAAC 2014. Abstract H-647c. ART-naive pts with HIV-1 RNA ≥ 5000 c/mL, CD4+ cell count > 50 cells/mm3 , eGFR > 70 mL/min (N = 153) DRV/COBI/FTC/TAF 800/150/200/10 mg QD (n = 103) Wk 48 DRV 800 mg QD (two 400-mg tablets) + COBI 150 mg QD + FTC/TDF 200/300 mg QD (n = 50) Wk 24
- 26. clinicaloptions.com/hiv Fall 2014 HIV Update DRV/COBI/FTC/TAF vs DRV + COBI + FTC/TDF: Virologic Suppression No cases of emergent drug resistance among 8 pts with viral rebound PBMC tenofovir diphosphate levels 6.5-fold higher in TAF vs TDF arm Plasma tenofovir exposure 91% lower in TAF vs TDF arm Mills A, ICAAC 2014. Abstract H-647c. Reproduced with permission. HIV-1RNA<50c/mL(%) 75 74 84 77 20 24 16 12 5 2 8 4 100 80 60 40 20 0 Tx Wk: 48 Virologic Success Virologic Failure No Data DRV/COBI/FTC/TAF DRV + COBI + FTC/TDF Weighted Difference (95% CI) Wk 24: 3.3 (-11.4 to 18.1) Wk 48: -6.2 (-19.9 to 7.4) 24 4824 4824
- 27. clinicaloptions.com/hiv Fall 2014 HIV Update DRV/COBI/FTC/TAF vs DRV + COBI + FTC/TDF: AEs and Lipid Changes 2 pts in each arm discontinued treatment for AEs – DRV/COBI/FTC/TAF: rash, substance dependence – DRV + COBI + FTC/TDF: worsening diarrhea, proximal renal tubulopathy Significantly greater increases in TC (P < .001), LDL cholesterol (P < . 001), and HDL cholesterol (P = .009) in TAF vs TDF arm; triglycerides increased in TAF arm vs small decrease in TDF arm (P = .007) Mills A, ICAAC 2014. Abstract H-647c. Reproduced with permission. AE Occurring in ≥ 10% Pts in TAF-Containing Arm, n (%) DRV/COBI/FTC/TAF (n = 103) DRV + COBI + FTC/TDF (n = 50) Diarrhea 22 (21) 13 (26) Fatigue 14 (14) 9 (18) Nausea 13 (13) 5 (10) Rash 12 (12) 4 (8)
- 28. clinicaloptions.com/hiv Fall 2014 HIV Update Lower mean increase in serum creatinine from BL to Wk 48 in TAF vs TDF arm: 0.06 mg/dL vs 0.09 mg/dL (P = .053) Less renal tubular proteinuria in TAF vs TDF arm (P = .003 for retinol binding protein/creatinine; P = .002 for β2-microglobulin/creatinine) DRV/COBI/FTC/TAF vs DRV + COBI + FTC/TDF: Other Outcomes Mills A, ICAAC 2014. Abstract H-647c. Reproduced with permission. 3 2 1 0 -1 -2 -3 -4 -5 P ≤ .001 P ≤ .001 -0.53 -2.09 -3.82 -0.84 24 48BL Wks Hip Mean%Change(95%CI) inBMDFromBL 3 2 1 0 -1 -2 -3 -4 -5 24 48BL Wks Spine P ≤ .001 P ≤ .003 -1.09 -3.86 -1.57 -3.62 DRV/COBI/FTC/TAF DRV + COBI + FTC/TDF
- 29. clinicaloptions.com/hiv Fall 2014 HIV Update AI438011: BMS-663068 in Treatment- Experienced Pts Phase IIb study; primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24 BMS-663068: HIV-1 attachment inhibitor prodrug, metabolized to BMS-626529 BMS-626529: novel HIV-1 attachment inhibitor; proposed MOA: binds gp120 to prevent viral attachment and host CD4+ cell entry; active against R5, R4, and dual tropic HIV-1 Brinson C, et al. Glasgow HIV 2014. Abstract O432A. BMS-663068 400 mg BID* + RAL + TDF (n = 50) BMS-663068 800 mg BID* + RAL + TDF (n = 49) BMS-663068 600 mg QD* + RAL + TDF (n = 51) BMS-663068 1200 mg QD* + RAL + TDF (n = 50) ATV/RTV 300/100 mg QD + RAL + TDF (n = 51) ART-exp’d pts with HIV-1 RNA ≥ 1000 c/mL, CD4+ cell count > 50 cells/mm3 , BMS-626529 IC50 < 100 nM (N = 251) *Trial also included 7-d BMS-663068 monotherapy substudy (10 pts/arm) before initiating combination therapy; mean HIV-1 RNA decrease with monotherapy: 0.7-1.5 log10 c/mL. Wk 96
- 30. clinicaloptions.com/hiv Fall 2014 HIV Update BMS-663068 in Treatment-Experienced Pts: Virologic Efficacy and AEs Virologic response rates generally similar across BMS- 663068 dose arms and ATV/RTV arm – Rates numerically lower with BL HIV-1 ≥ 100,000 c/mL vs BL HIV-1 RNA < 100,000 c/mL except in BMS-663068 1200 mg QD arm Virologic response rates generally similar across BMS- 626529 baseline IC50 subgroups, but few pts in some subgroups BMS-663068 arms: 4 pts discontinued for AEs; 4% to 8% experienced serious AEs Brinson C, et al. Glasgow HIV 2014. Abstract O432A.
- 31. clinicaloptions.com/hiv Fall 2014 HIV Update Protocol 007: Doravirine + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, 2-part, dose-finding phase II study Safety endpoints: CNS AEs at Wk 8; AEs and laboratory parameters Wk 48; efficacy endpoints: HIV-1 RNA < 40 c/mL, < 200 c/mL and CD4+ cell count change at Wk 48 Gatell JM, et al. Glasgow HIV 2014. Abstract O434. Doravirine 25 mg QD (n = 41) Doravirine 50 mg QD (n = 43) Doravirine 100 mg QD (n = 42) Doravirine 200 mg QD (n = 41) Efavirenz 600 mg QD (n = 43) Part 1: ART-naive pts with HIV-1 RNA ≥ 1000 c/mL, CD4+ cell count ≥ 100 cells/mm3 (N = 210) Part 2: ART-naive pts with HIV-1 RNA ≥ 1000 c/mL, CD4+ cell count ≥ 100 cells/mm3 (N = 132) Doravirine 100 mg QD Doravirine 100 mg QD Doravirine 100 mg QD Doravirine 100 mg QD Efavirenz 600 mg QD Doravirine 100 mg QD (n = 66) Efavirenz 600 mg QD (n = 66) Wk 96Wk 48Wk 36
- 32. clinicaloptions.com/hiv Fall 2014 HIV Update Doravirine + TDF/FTC: Virologic Response by Baseline HIV-1 RNA Part 1: ad hoc analysis, Wk 48 (observed failure) Gatell JM, et al. Glasgow HIV 2014. Abstract O434. Reproduced with permission. Baseline HIV-1 RNA ≤ 100,000 c/mL Baseline HIV-1 RNA > 100,000 c/mL 88 89 86 85 87 74 25 27 28 27107 27 96 89 89 89 91 82 25 27 28 27107 27 < 40 c/mL < 200 c/mL < 40 c/mL < 200 c/mL 64 64 73 92 73 83 91 73 100 92 89 92 11 11 11 12 45 12 11 11 11 12 45 12 100 80 60 40 20 0 n = Pts(%) DOR 25 mg DOR 50 mg DOR 100 mg DOR 200 mg All DOR EFV Wk 48 HIV-1 RNA Wk 48 HIV-1 RNA
- 33. clinicaloptions.com/hiv Fall 2014 HIV Update Doravirine + TDF/FTC: Wk 48 Resistance Gatell JM, et al. Glasgow HIV 2014. Abstract O434. Reproduced with permission. Outcome, n (%) Doravirine, All Doses (n = 166) Efavirenz 600 mg (n = 42) Virologic failure* ≥ 40 c/mL 27 (16.3) 6 (14.3) Virologic failure* ≥ 200 c/mL 6 (3.6) 1 (2.4) Resistance testing performed† 6 (3.6) 1 (2.4) NNRTI mutations detected (K101K/E) 1 (0.6)‡ 0 NRTI mutations detected 0 0 *Virologic failure: nonresponse (HIV-1 RNA < 40 or < 200 c/mL by Wk 24 not achieved) or rebound (2 consecutive measures of HIV-1 RNA ≥ 40 or ≥ 200 c/mL, > 1 wk apart or after Wk 24 in pts with initial response). † HIV-1 RNA > 500 c/mL required for resistance testing. ‡ HIV-1 RNA resuppressed at Wk 48 but rebounded; pt discontinued due to noncompliance.
- 35. clinicaloptions.com/hiv Fall 2014 HIV Update TURQUOISE-I: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in HIV/GT1 HCV Pts Open-label phase II/III trial Inclusion criteria: GT1; compensated cirrhosis (Child-Pugh A) allowed; DAA naive but pegIFN/RBV naive or experienced; HIV-1 RNA < 40 c/mL on ATV or RAL regimen; CD4+ cell count ≥ 200 or %CD4+ ≥ 14% 52% on ATV, 48% on RAL in 12-wk arm; 38% on ATV, 62% on RAL in 24-wk arm; 19% with cirrhosis Primary endpoint: SVR12 Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 32) Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV (n = 31) Wk 24 Paritaprevir/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day. DAA-naive HIV-infected pts with GT1 HCV infection (N = 63) Wk 12 Eron JJ, et al. Glasgow HIV 2014. Abstract O222.
- 36. clinicaloptions.com/hiv Fall 2014 HIV Update TURQUOISE-I: Efficacy (ITT) and Resistance Results VF with RAVs in all 3 HCV target genes occurred in 2 pts with genotype 1a HCV, previous null response to pegIFN/RBV, and cirrhosis VF (posttreatment) without RAVs occurred in 2 HCV treatment-naive pts with genotype 1a HCV – Genetic analysis strongly supported HCV reinfection with different isolate – Both pts MSM who reported high-risk sexual practices posttreatment Eron JJ, et al. Glasgow HIV 2014. Abstract O222. Reproduced with permission. 12 wks (n = 31) 24 wks (n = 32) SVR12(%) n/N = *2 pts in 24-wk arm had HCV viremia recurrence suspected to be caused by HCV reinfection. 100 80 60 40 20 0 Overall Atazanavir Raltegravir 29/ 31 29/ 32 15/ 16 12/ 12 14/ 15 17/ 20 93.5 90.6 93.8 100 93.3 85.0*
- 37. clinicaloptions.com/hiv Fall 2014 HIV Update Paritaprevir/RTV/Ombitasvir + Dasabuvir: Drug–Drug Interactions With ART Randomized, multiple-dose phase I study in healthy volunteers 1. Khatri A, et al. ICAAC 2014. Abstract V-483. 2. Khatri A, et al. ICAAC 2014. Abstract V-484. Coadministered Drugs* Days Clinically Relevant PK Interactions Recommended Dose Adjustments Safety/Tolerability Concerns 3 DAAs + FTC/TDF[1] 7-14 None None None 3 DAAs + RAL[1] 14 None None None 3 DAAs + RPV[1] 14 ↑ RPV exposure Do not coadminister None Paritaprevir/RTV + dasabuvir + EFV/FTC/TDF[1] 14 NA Do not coadminister 9/16 discontinued for AEs (GI and ALT/AST ↑) 3 DAAs + ATV + RTV QAM or QPM[2] 14 None None None 3 DAAs + DRV + RTV (QAM, QPM, or BID)[2] 14 None None None 3 DAAs + LPV/RTV (QPM or BID)[2] 14 None; RTV dose 300 mg/day due to dual RTV-containing FDCs Do not coadminister Increase GI AEs *Paritaprevir/RTV/ombitasvir administered in morning, dasabuvir dosed morning and evening; RTV dosed with ATV and DRV omitted when administering in the morning because of RTV presence in 3 DAAs.
- 38. Linkage to Care
- 39. clinicaloptions.com/hiv Fall 2014 HIV Update Kaiser Permanente HIV Care Cascade in 2010-2012 According to Age and Sex CDC data show HIV care performance differs by age and sex[1] KP integrated care system includes 9 states plus Washington DC, > 9 million members, > 22,000 HIV-infected members in 2013 Data show improved care performance in KP system vs CDC report[2] Current analysis investigated differences in HIV care performance by age or sex among KP members 13 yrs of age or older with ≥ 8 mos of membership in study yr from 2010-2012[3] – Male: 87% – Aged younger than 35 yrs: 10% to 11%; aged 35-54 yrs: 57% to 61%; aged 55 yrs or older: 29% to 32% 1. CDC fact sheet: HIV in the United States: the stages of care. 2012. 2. Horberg M, et al. CROI 2013. Abstract 1033. 3. Horberg M, et al. IDWeek 2014. Abstract 88.
- 40. clinicaloptions.com/hiv Fall 2014 HIV Update HIV Care Cascade Measured Over Multiple Time Periods Varies by Age and Sex Higher rate of linkage to care, ART prescription, and viral suppression in men vs women in 2010 and 2011, but no significant difference between sexes in 2012; higher rate of retention in care in women vs men in all yrs Higher rates of retention in care, ART prescription, and viral suppression with older age in all 3 yrs Horberg M, et al. IDWeek 2014. Abstract 88. Reproduced with permission. *Care linkage: visit/CD4+ count within 90 days of diagnosis/enrollment. † Care retention: ≥ 2 medical visits ≥ 60 days apart. 100 80 60 40 20 0 2010 2011 2012 2010 2011 2012 2010 2011 2012 2010 2011 2012 Linked to Care* Retained in Care† Filled ART ≥ 3 Mos HIV-1 RNA < 200 c/mL at Last Measure Aged younger than 35 yrs Aged 35-54 yrs Aged 55 yrs and older CompletedCareStep(%) P < .05 P < .05 P < .05
- 41. Go Online for More CCO Coverage of ICAAC, IDWeek, and HIV Glasgow! CME-certified Expert Analysis with expert commentary on all the key studies clinicaloptions.com/hiv/Conference Coverage/Fall 2014 HIV
Editor's Notes
- This slide lists the faculty who were involved in the production of these slides.
- This slide lists the disclosure information of the faculty involved in the development of these slides.
- ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; FTC, emtricitabine; ITT, intent-to-treat; QD, once daily; RTV, ritonavir; TDF, tenofovir. Jürgen K. Rockstroh, MD: At ICAAC, Gallant and colleagues[1] presented Week 144 data from a randomized phase III trial comparing ritonavir-boosted atazanavir with cobicistat-boosted atazanavir, each in combination with emtricitabine/tenofovir disoproxil fumarate, in 692 treatment-naive patients with HIV-1 RNA ≥ 5000 copies/mL. The primary endpoint of this study was HIV-1 RNA &lt; 50 copies/mL at Week 48, and a US Food and Drug Administration (FDA) snapshot analysis at that time point demonstrated the noninferiority of cobicistat to ritonavir.[2]
- ATV, atazanavir; COBI, cobicistat; FDA, US Food and Drug Administration; FTC, emtricitabine; ITT, intent-to-treat; RTV, ritonavir; TDF, tenofovir. Jürgen K. Rockstroh, MD: Results of the current analysis show that cobicistat remains noninferior to ritonavir for virologic efficacy through Week 144.[1] At Week 144, 72% of patients treated with cobicistat-boosted atazanavir had HIV-1 RNA &lt; 50 copies/mL vs 74% of those treated with ritonavir-boosted atazanavir. The mean CD4+ cell count increases evaluated at Week 144 were also comparable between the 2 arms at 310 vs 332 cells/mm3, respectively. Joseph J. Eron, Jr., MD: These data illustrate the comparability of cobicistat, which is now available as a single agent in the United States, to ritonavir in terms of its ability to boost atazanavir and provide similar antiviral activity between the regimens. The proportions of patients with HIV-1 RNA &lt; 50 copies/mL in this study are very similar to many other studies that we have seen in recent years. Jürgen K. Rockstroh, MD: Yes, as a clinician, it is always reassuring to see long-term data confirming the durability of the regimen rather than relying on Week 48 efficacy results alone. It is also worth noting that the similar virologic outcomes in the 2 treatment arms suggest that the cobicistat-containing regimen does not have an efficacy advantage over the ritonavir-containing regimen.
- AEs; adverse events; ATV, atazanavir; BL, baseline; COBI, cobicistat; Cr, creatinine; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; IQR, interquartile range; RTV, ritonavir; TDF, tenofovir. Jürgen K. Rockstroh, MD: One important difference between the 2 agents is the greater increase in serum creatinine and the greater decrease in estimated glomerular filtration rate observed with cobicistat vs ritonavir.[1] Although this difference arises from the known inhibitory effect of cobicistat on tubular creatinine secretion rather than true renal damage, and it occurs within hours of taking the drug without additional progression over time, the observed creatinine elevations can complicate management in some patients, for example, those with borderline creatinine levels at baseline. Joseph J. Eron, Jr., MD: I agree that these changes in creatinine level and creatinine clearance rate can complicate management in patients with elevated baseline creatinine levels, particularly for patients being managed by additional physicians or care providers who may not be aware of the benign association between cobicistat and creatinine changes. In addition, these data highlight the effects of ritonavir on tubular creatinine secretion, although less pronounced than seen with cobicistat. One advantage of the single-agent formulation of cobicistat is the option to avoid coadministration with tenofovir disoproxil fumarate if desired. For example, cobicistat can be administered in patients with borderline renal function for whom tenofovir DF administration would not be appropriate. Jürgen K. Rockstroh, MD: In the current era of HIV therapy, the time interval between clinic visits is becoming slightly longer because of cost restraints, at least in Europe, creating challenges in patients requiring frequent renal monitoring. For example, patients who have maintained undetectable HIV-1 RNA into Year 6 of therapy may be seen in the office as infrequently as every-6-month intervals. In addition, as the HIV-infected population ages, clinicians will see increasing numbers of patients with elevated creatinine levels and possibly some targeted organ damage due to other aging-related comorbidities such as arterial hypertension and diabetes. It is worth noting that other newer antiretroviral agents, such as dolutegravir, also inhibit tubular creatinine secretion. As a result, clinicians may be observing more frequent creatinine increases with initiation of antiretroviral therapy than they would like with these newer agents, and these increases may require more frequent monitoring. Joseph J. Eron, Jr., MD: I agree. Jürgen K. Rockstroh, MD: Regarding the selection of cobicistat vs ritonavir as a boosting agent for atazanavir, in my opinion the decision for clinicians in Europe will depend on if atazanavir and cobicistat become available as a fixed-dose coformulation. Having the pharmacoenhancer and the PI in 1 tablet to ensure adequate drug levels, particularly for an adherence-challenged patient, will be an important feature.
- ATV, atazanavir; COBI, cobicistat; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides. Jürgen K. Rockstroh, MD: When the investigators from this study assessed changes in lipid levels during treatment, there were no statistically significant differences, although increases in total and low density lipoprotein cholesterol as well as triglycerides were numerically higher with the ritonavir-boosted vs cobicistat-boosted regimen.[1] In general, the lipid changes appeared to be typical of those observed with PI-based therapy particularly for total cholesterol and triglycerides. Additional treatment-emergent resistance occurred in 9 patients in the cobicistat arm and 7 patients in the ritonavir arm between Weeks 96 and 144.[1] Of importance, there were no cases of primary PI resistance through Week 144, which is one of the major benefits of boosted PIs, particularly among patients for whom adherence is a concern. The high barrier to resistance provides assurance that if virologic failure does occur, it will not be at the cost of developing PI resistance. Joseph J. Eron, Jr., MD: Yes, that is a critical point. If cobicistat is to be considered noninferior to ritonavir for boosting a PI, it is essential that all features are at least equivalent, including virologic efficacy as well as tolerability, toxicity, and, as Dr. Rockstroh noted, the resistance
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; CrCl, creatinine clearance; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; RAL, raltegravir; RTV; ritonavir; TDF, tenofovir; VL, viral load. Joseph J. Eron, Jr., MD: Three large phase III trials have evaluated dolutegravir in treatment-naive patients: SPRING-2,[3] SINGLE,[4] and FLAMINGO.[5] The 2014 fall HIV conferences provided follow-up data on 2 of those trials: the active-controlled, double-blind SINGLE trial, which compared dolutegravir plus abacavir/lamivudine with the fixed-dose combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate in 833 patients,[4] and the open-label FLAMINGO trial, which compared dolutegravir plus 2 NRTIs with darunavir/ritonavir plus 2 NRTIs in 484 patients.[5] Either emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine was chosen, at the discretion of the investigator.
- 3TC, lamivudine; ABC, abacavir; AE, adverse event; AUC, area under the curve; d/c, discontinuation; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PK, pharmacokinetics; TDF, tenofovir. Joseph J. Eron, Jr., MD: The 144-week follow-up results from the SINGLE trial demonstrated that, similar to the Week 48 report,[6] the dolutegravir-based regimen remained superior to the efavirenz-based regimen for virologic efficacy.[4] At Week 144, 71% of patients receiving dolutegravir and 63% of patients receiving efavirenz had HIV-1 RNA &lt; 50 copies/mL. This difference was due predominantly to fewer adverse event–related discontinuations with dolutegravir. Another important finding was the lack of any treatment-emergent resistance mutations in the dolutegravir arm through Week 144, whereas 1 patient developed NRTI resistance mutations and 6 patients developed NNRTI resistance mutations in the efavirenz arm. Finally, the CD4+ cell count increase was also greater with dolutegravir vs efavirenz at 379 cells/mm3 vs 332 cells/mm3, respectively (P = .003). It is important to note that at 96 weeks, the study became open-label and patients were given the choice of whether to continue on study treatment. This feature contributed to the decrease in the proportion of patients with HIV-1 RNA &lt; 50 copies/mL in both arms from Week 48 to Week 144. However, the virologic failure rate remained low at Week 144. In a separate pharmacokinetic study evaluating the interaction between metformin and dolutegravir in HIV-uninfected individuals, dolutegravir coadministration resulted in an almost 2-fold increase in plasma metformin exposure.[7] Before this analysis, an interaction between these 2 drugs was predicted but had not been formally studied. Jürgen K. Rockstroh, MD: Yes, the results of the pharmacokinetic analysis show the need for careful dose selection and vigilance for metformin-related adverse effects, particularly lactic acidosis, with the coadministration of dolutegravir. The Week 144 data from the SINGLE trial are noteworthy for the continued lack of integrase-associated resistance variants.[4] When considering integrase inhibitors as a class, although there have been few cases of virologic failure to first-line integrase inhibitor therapy, there have been cases of drug resistance. Therefore, the data with dolutegravir raise the question of whether the genetic barrier to resistance is higher for this agent vs other integrase inhibitors or whether resistance will ultimately develop over time in some patients receiving dolutegravir. In my opinion, this is a highly relevant clinical question because a very high barrier to resistance has thus far been a feature somewhat unique to the boosted PI class. Joseph J. Eron, Jr., MD: I agree. Currently available data from the SPRING-2 study[3] as well as long-term data through 144 weeks in the SINGLE study[4] and through 96 weeks in the FLAMINGO study[5] that we will discuss next have to date shown no treatment-emergent integrase inhibitor resistance or NRTI resistance with first-line dolutegravir-based therapy. It is still too early to know for certain if the dolutegravir barrier to resistance is as high as that of the boosted PIs, but based on multiple studies published or presented to date, it is clear that dolutegravir has a greater barrier to resistance than earlier-generation integrase inhibitors. Jürgen K. Rockstroh, MD: It will also be important to determine if resistance develops in patients with more advanced disease. The clinical trial “stress test” for new agents occurs in patients with high HIV-1 RNA levels and low CD4+ cell counts at baseline. Such patients are no longer well represented in HIV clinical trials, and the overall incidence of treatment-emergent drug resistance is decreasing in trials involving treatment-naive patients. Joseph J. Eron, Jr., MD: I agree. It will be interesting to see if any resistance to dolutegravir emerges in real-world clinical practice settings where these populations are better represented.
- AE, adverse event; BL, baseline; d/c, discontinuation; DRV, darunavir; DTG, dolutegravir; NR, not reported; RTV, ritonavir. Joseph J. Eron, Jr., MD: As mentioned earlier, FLAMINGO was an open-label trial comparing dolutegravir plus 2 NRTIs with darunavir/ritonavir plus 2 NRTIs in 484 treatment-naive patients.[5] Previously published Week 48 data showed that dolutegravir was superior to darunavir/ritonavir for the primary endpoint of HIV-1 RNA &lt; 50 copies/mL at Week 48,[8] and this efficacy advantage persists in the current 96-week analysis[5]: At Week 96, 80% of patients treated with dolutegravir and 68% of patients treated with darunavir/ritonavir had HIV-1 RNA levels &lt; 50 copies/mL. Similar to the SINGLE trial,[4] there were fewer adverse event–related discontinuations in the dolutegravir arm vs the comparator.[5] In FLAMINGO, no patient in either arm developed treatment-emergent resistance mutations through 96 weeks, again raising the question of whether the dolutegravir barrier to resistance is comparable to that of boosted PIs. As with cobicistat, dolutegravir inhibits tubular creatinine secretion in the kidney, resulting in a similar increase in serum creatinine despite the fact that the 2 drugs inhibit different creatinine transporter proteins.
- 3TC, lamivudine; ABC, abacavir; BL, baseline; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Joseph J. Eron, Jr., MD: A subgroup analysis of Week 96 data from FLAMINGO study showed that the difference in efficacy between the 2 treatment arms was magnified among patients with high baseline HIV-1 RNA levels.[5] Among patients with baseline HIV-1 RNA &gt; 100,000 copies/mL, 82% treated with dolutegravir achieved HIV-1 RNA levels &lt; 50 copies/mL vs 52% for patients treated with darunavir/ritonavir. However, it is important to note that the number of patients in the high HIV-1 RNA subgroup was relatively small, constituting only one fourth of the total study population (122/484). A subgroup analysis of virologic response according to background NRTIs showed similar efficacy between dolutegravir plus abacavir/lamivudine and dolutegravir plus emtricitabine/tenofovir disoproxil fumarate, although this was not a randomized comparison controlled for other factors such as baseline HIV-1 RNA or CD4+ cell count because investigators selected the NRTI pairs. Therefore, it is difficult to draw definitive conclusions from this analysis. Jürgen K. Rockstroh, MD: Regarding the difference in virologic response rates among patients with high baseline HIV-1 RNA, it is useful to consider that viral kinetics differ between integrase inhibitors and boosted PIs such that the decline in HIV-1 RNA is more rapid with integrase inhibitors and, therefore, undetectable HIV-1 RNA is reached more quickly. This difference becomes more pronounced in patients with baseline HIV-1 RNA &gt; 100,000 copies/mL because it takes longer for this group to reach HIV-1 RNA &lt; 50 copies/mL. The slower decline in HIV-1 RNA with PIs may mean that some patients are classified as having virologic failure at a given time point, despite the fact that they may achieve HIV-1 RNA &lt; 50 copies/mL at a later time. Because there is no emergence of drug resistance, there is no adverse clinical consequence from the delay in achieving undetectable HIV-1 RNA. Joseph J. Eron, Jr., MD: I agree. The decline in HIV-1 RNA is slower with PIs, especially in patients with very high HIV-1 RNA, but this likely is of little clinical consequence.
- BL, baseline; DRV, darunavir; DTG, dolutegravir; HDL, high density lipoprotein; LDL, low density lipoprotein; RTV, ritonavir; TC, total cholesterol. Joseph J. Eron, Jr., MD: Lipid changes through Week 96 were smaller in the dolutegravir arm vs the darunavir/ritonavir arm, including the increase in total cholesterol/high density lipoprotein cholesterol ratio.[5] Jürgen K. Rockstroh, MD: The difference in mean change in total cholesterol/high density lipoprotein cholesterol ratio between arms in this study is important because this ratio has demonstrated clinical relevance for cardiovascular risk, and often in clinical trials that show significant differences in lipid parameters between treatment arms, changes in this ratio remain similar, which was not the case in FLAMINGO.[5]
- ART, antiretroviral therapy; CrCl, creatinine clearance; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Jürgen K. Rockstroh, MD: At the HIV Drug Therapy meeting in Glasgow, United Kingdom, Carey and colleagues[9] reported data from the randomized double-blind ENCORE1 trial, comparing 400 mg vs 600 mg of once-daily efavirenz, each in combination with emtricitabine/tenofovir disoproxil fumarate in 630 treatment-naive patients. It is hypothesized that the 600-mg dose of efavirenz may be higher than necessary, given that this same drug dose is equally effective for patients with vastly different body masses. This study evaluated whether virologic efficacy can be achieved with a lower efavirenz dose and if a lower dose may be associated with an improved tolerability profile. Some data suggest that high efavirenz levels are associated with an increased risk for central nervous system toxicity.
- AE, adverse event; BL, baseline; EFV, efavirenz; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Jürgen K. Rockstroh, MD: The graph shown here depicts the change in HIV-1 RNA levels from baseline with the 2 different efavirenz doses and demonstrates that the virologic efficacy of both doses is very similar, with a mean difference between arms in HIV-1 RNA change from baseline of -0.02 log10 copies/mL (P = .74).[9] Notably, the mean increase in CD4+ cell count from baseline was significantly greater with 400-mg vs 600-mg efavirenz (P = .03). In addition, the rate of efavirenz-related adverse events was significantly lower with the 400-mg vs the 600-mg dose at 37.7% vs 47.9% (P = .01), and there was a trend toward a lower rate of discontinuation for efavirenz-related adverse events with the lower dose. Finally, the frequency of treatment-emergent NNRTI resistance was similar in both treatment arms. In my opinion, this is an important study with useful implications, particularly for clinicians and patients in resource-limited settings. Joseph J. Eron, Jr., MD: There are 2 important points to note about this study. The first is that it has been appropriately blinded to assess tolerability and toxicity. Second, although the similar virologic efficacy between the 2 doses is critical, there was a modest CD4+ cell count advantage with the lower dose of efavirenz.[9] This is particularly of interest given that efavirenz in combination with emtricitabine/tenofovir disoproxil fumarate has typically lagged slightly behind in CD4+ cell count response when compared with other regimens in clinical trials. A recent example is the significant difference in CD4+ cell count increases observed in the previously discussed SINGLE trial (+379 cells/mm3 with dolutegravir plus abacavir/lamivudine vs +332 cells/mm3 with efavirenz/emtricitabine/tenofovir disoproxil fumarate; P = .003).[4] The signal in the ENCORE1 trial suggests that there may be an effect of efavirenz concentrations on CD4+ cell count recovery.[9] Jürgen K. Rockstroh, MD: Yes, I agree. Another well-powered example of reduced CD4+ cell count response with efavirenz is the ACTG 5142 trial comparing lopinavir/ritonavir with efavirenz, in which the virologic failure rate was higher with lopinavir/ritonavir, but the CD4+ cell count increase was higher with the boosted PI.[10] It is interesting to see that the immune response with efavirenz is greater with the lower dose.
- EFV, efavirenz. Joseph J. Eron, Jr., MD: At IDWeek, Nkhoma and colleagues[11] reported findings from what was termed a “real-world” assessment of suicidality risk among patients initiating efavirenz. In this study, investigators retrospectively evaluated data from a commercial insurance database and a multistate Medicaid database to examine suicidality among patients initiating efavirenz-containing vs efavirenz-free antiretroviral regimens for HIV infection from 2006-2013. The primary outcome was suicidality based on medical coding for suicidal ideation or suicide attempt. However, this analysis does not capture successful suicide attempts because there is not a medical claim for suicide in the medical claims database. The secondary outcomes included suicide attempt and injuries consistent with suicide attempt. After adjusting for differences in patient characteristics between the efavirenz and efavirenz-free groups, the HRs for the primary outcome of suicidality demonstrated no effect of efavirenz on suicidality in either database.[11] The adjusted HR for the commercial database was 1.03 (95% CI: 0.64-1.67) and for the Medicaid database was 0.90 (95% CI: 0.62-1.32). The background for this study is that several recent analyses have reported conflicting data on the association between efavirenz use and suicidality. A retrospective analysis of pooled data from 4 ACTG trials involving treatment-naive patients who were randomized to efavirenz-containing or efavirenz-free regimens demonstrated that efavirenz-based therapy was associated with a 2-fold increase in the risk of suicidality vs efavirenz-free therapy.[12] However, a separate analysis from the US Food and Drug Administration Adverse Event Reporting system found that efavirenz was not associated with a disproportionate incidence of suicidality compared with other antiretroviral agents.[13]
- EFV, efavirenz; SD, standard deviation. Joseph J. Eron, Jr., MD: A comparison of various patient characteristics between those treated with efavirenz and those treated with efavirenz-free regimens in both databases showed that efavirenz-treated patients were more likely to be men and to have an AIDS-defining illness (in the commercial database only), were less likely to have depression, drug dependence, anxiety, or schizophrenia, and were less likely to be receiving second-generation antipsychotics or antidepressants (commercial database only).[11] These comparisons suggest that there may be bias in how physicians select candidates for efavirenz-based regimens and that patients treated with efavirenz may have a lower baseline risk for suicidality. Although the investigators attempted to control for this bias, it may not be possible to control for all variables affecting the decision of whether to recommend efavirenz. Jürgen K. Rockstroh, MD: The findings from this analysis are interesting in light of the discussion initiated by the ACTG trial analysis. Another report presented at the HIV Drug Therapy meeting in Glasgow was from a study examining the association of efavirenz with suicide or death related to psychiatric illness in the D:A:D cohort.[14] The analysis included an impressive 371,333 person-years of follow-up and it did not identify an association. However, if clinicians are less likely to administer efavirenz to someone who has a history of depression or a suicide attempt in the past, that will clearly lead to an intrinsic bias. That is true. I cannot come up with a definitive conclusion given the conflicting evidence. In the past, only a few convenient alternatives to the efavirenz-based single-tablet regimen were available, but now there are multiple alternatives. In patients at risk for suicide or in those with depression, many clinicians would choose an alternative.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ARV, antiretroviral; DRV, darunavir; FDA, US Food and Drug Administration; HCV, hepatitis C virus; ITT, intent-to-treat; QD, once daily; RTV, ritonavir; TDF, tenofovir; ZDV, zidovudine. Jürgen K. Rockstroh, MD: In the randomized, open-label phase IIIb PROTEA trial, switching from a virologically suppressive first-line antiretroviral therapy regimen to ritonavir-boosted darunavir was compared with switching to ritonavir-boosted darunavir plus 2 NRTIs in 273 patients.[15,16] Enrollment required HIV-1 RNA &lt; 50 copies/mL on first-line HIV treatment and a CD4+ cell count nadir &gt; 100 cells/mm3. The NRTI pair was selected by the investigator and could include combinations involving abacavir, lamivudine, zidovudine, tenofovir disoproxil fumarate, or emtricitabine. The average duration of initial antiretroviral treatment was long at 5.5 years. As context, there is a strong interest in the use of boosted PI monotherapy in Europe as a strategy to decrease the cost burden by eliminating the NRTIs.
- DRV, darunavir; ITT, intent-to-treat; RTV, ritonavir. Jürgen K. Rockstroh, MD: Virologic response rates (HIV-1 RNA &lt; 50 copies/mL) at Week 48 were 86% with ritonavir-boosted darunavir monotherapy vs 95% with ritonavir-boosted darunavir plus 2 NRTIs, demonstrating an efficacy advantage for inclusion of 2 NRTIs.[15,16] This result is consistent with several previous studies that have shown an advantage when the NRTIs are retained in the regimen.[17,18] When the investigators evaluated virologic response according to nadir CD4+ cell count, the difference between the 2 switch strategies was much more pronounced among patients with a CD4+ cell count nadir &lt; 200 cells/mm3 who are generally considered slightly more difficult to treat. In this subgroup, only 66% of patients switched to ritonavir-boosted darunavir monotherapy achieved HIV-1 RNA &lt; 50 copies/mL at Week 48 vs 97% of patients switched to ritonavir-boosted darunavir plus 2 NRTIs. In my opinion, this finding makes it clear that switching to boosted PI monotherapy is not advisable for patients starting with a low CD4+ cell count. Joseph J. Eron, Jr., MD: Examining patients with a CD4+ cell count nadir &lt; 200 cells/mm3 was a clever subanalysis. As Dr. Rockstroh noted, despite the fact that patients in this study had experienced virologic suppression on average for many years (average duration of initial antiretroviral treatment: 5.5 years), boosted PI monotherapy seemed to be insufficient for those with a low CD4+ cell count nadir.[15,16] It is not known whether this finding is related to the worsened ongoing inflammation observed for patients with a low nadir. One hypothesis is that the increased inflammation in these patients is more likely to spur bursts of low-level viral replication that the boosted PI alone cannot keep in check. Although the mechanism is not known, this observation is very interesting and might prompt investigators to reevaluate past switch studies to evaluate virologic suppression rates in patients with low nadir CD4+ cell counts.
- AE, adverse event; DRV, darunavir; RTV, ritonavir. Jürgen K. Rockstroh, MD: The adverse event data demonstrated slightly higher rates of overall adverse events in the ritonavir-boosted darunavir monotherapy switch arm. Therefore, there was no clear safety advantage from removing the NRTIs.[15,16] Joseph J. Eron, Jr., MD: The lack of safety benefit from removing NRTIs underscores that the primary reason for evaluating this strategy is cost savings. Several studies have compared switching to boosted PI monotherapy vs switching to a boosted PI plus 2 NRTIs, without demonstrating any considerable safety advantage.[17,19]
- ART, antiretroviral therapy; COBI, cobicistat; DRV, darunavir; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; FTC, emtricitabine; ITT, intent-to-treat; QD, once daily; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Jürgen K. Rockstroh, MD: At ICAAC, Mills and colleagues[20] reported on a randomized, double-blind, placebo-controlled phase II study comparing fixed-dose darunavir/cobicistat/emtricitabine/tenofovir alafenamide vs darunavir boosted by cobicistat plus emtricitabine/tenofovir disoproxil fumarate in 153 treatment-naive patients. This trial examines the first fully fixed-dose combination involving a PI, and cobicistat is used as the PI boosting agent in both treatment arms. The randomization was 2:1, with 103 patients receiving darunavir/cobicistat/emtricitabine/tenofovir alafenamide and 50 patients treated with darunavir, cobicistat, and emtricitabine/tenofovir disoproxil fumarate.
- COBI, cobicistat; DRV, darunavir; FTC, emtricitabine; PBMC, peripheral blood mononuclear cell; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; Tx, treatment. Jürgen K. Rockstroh, MD: The proportions of patients with HIV-1 RNA &lt; 50 copies/mL at Week 48 were comparable between treatment arms at 77% with darunavir/cobicistat/emtricitabine/tenofovir alafenamide and 84% with darunavir, cobicistat, and emtricitabine/tenofovir disoproxil fumarate.[20] There were no cases of treatment-emergent drug resistance among the 8 patients with viral rebound, which is reassuring particularly because data are still accruing for cobicistat. The results of this study continue to support the efficacy of cobicistat as a pharmacoenhancer. The analysis of drug exposure levels showed that tenofovir diphosphate levels in peripheral blood mononuclear cells were 6.5-fold higher among patients in the tenofovir alafenamide arm vs the tenofovir disoproxil fumarate arm.[20] Moreover, plasma tenofovir exposure was 91% lower in the tenofovir alafenamide arm.
- AE, adverse event; COBI, cobicistat; DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir disoproxil fumarate. Jürgen K. Rockstroh, MD: Regarding adverse events, the incidence of gastrointestinal toxicity was similar between the 2 treatment arms.[20] The incidence of rash was numerically slightly higher in patients receiving the fixed-dose, tenofovir alafenamide–containing combination, but it is difficult to draw conclusions on that difference given the low number of cases (n = 4) in the tenofovir disoproxil fumarate arm. It is also worth mentioning that the increases in total cholesterol (P &lt; .001), low density lipoprotein cholesterol (P &lt; .001), and high density lipoprotein cholesterol (P = .009) were significantly higher among patients receiving tenofovir alafenamide,[20] which is to be expected considering that the plasma tenofovir levels were lower in this group. The cholesterol-lowering effects traditionally associated with tenofovir disoproxil fumarate result from systemic exposure to tenofovir, which is dramatically reduced with tenofovir alafenamide.
- BL, baseline; BMD, bone marrow density; COBI, cobicistat; DRV, darunavir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Jürgen K. Rockstroh, MD: The most interesting safety outcome from this study is the difference in serum creatinine increases between the 2 treatment arms.[20] The mean increase from baseline to Week 48 was lower in the tenofovir alafenamide arm vs the tenofovir disoproxil fumarate arm with a P value approaching statistical significance (P = .053), suggesting that the lower tenofovir plasma levels may have had a positive impact on creatinine outcomes. There was also less renal tubular proteinuria in the tenofovir alafenamide arm (P = .003 for retinol binding protein/creatinine; P = .002 for β2-microglobulin/creatinine). In the bone mineral density analysis for hip and spine, much smaller declines occurred in the tenofovir alafenamide vs tenofovir disoproxil fumarate arm (P ≤ .001 for both regions), as was expected.[20] Taken together, the findings from this study confirm that tenofovir alafenamide offers an improved bone and renal safety profile vs tenofovir disoproxil fumarate. Joseph J. Eron, Jr., MD: This is an important study given that clinicians have not had the opportunity to give a boosted PI within the context of a single-tablet regimen. Therefore, the fixed-dose darunavir/cobicistat/emtricitabine/tenofovir alafenamide regimen has an advantage based on convenience alone. As Dr. Rockstroh noted, it appears that including tenofovir alafenamide in this single-tablet boosted PI regimen also has the advantage of fewer renal and bone-related adverse events vs tenofovir disoproxil fumarate. Of course, it will be important to assess longer-term data on renal toxicity before making firm conclusions about this difference, but there is clearly a reduced effect on bone mineral density. These results are consistent with the renal and bone safety outcomes of another trial that compared the single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide vs elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.[21] Recall that when tenofovir disoproxil fumarate is administered with a boosted PI, the largest bone mineral density changes usually occur during the first 24-48 weeks of therapy. Certainly, those changes are lessened substantially with tenofovir alafenamide in this study.[20] It is important to point out that this is a phase II trial. As noted earlier, there was a slight numerical difference in the proportion of patients with HIV-1 RNA &lt; 50 copies/mL at Week 48, but the number of patients in the study is relatively small at 153.[20] In my opinion, a larger comparative trial of these regimens is needed to confirm the efficacy equivalence, although it appears likely that tenofovir alafenamide represents a substantial advance over tenofovir disoproxil fumarate. Jürgen K. Rockstroh, MD: I agree. Moreover, a phase II trial is too small to address questions about whether the single-tablet regimen translates to improved adherence and, subsequently, improved efficacy. Another important issue in clinical practice that could be affected by the use of tenofovir alafenamide is the fact that as HIV-infected cohorts advance in age, tenofovir disoproxil fumarate and PI use is emerging as one of the driving factors of more frequent renal complications. In ACTG A5224s, a substudy of the A5202 trial comparing boosted atazanavir vs efavirenz, each in combination with either emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine, the greatest declines in glomerular filtration rate occurred among patients receiving boosted atazanavir with emtricitabine/tenofovir disoproxil fumarate.[22] These data suggest that tenofovir exposure is higher when tenofovir disoproxil fumarate is coadministered with a boosted PI. It follows that the renal and bone effects of tenofovir disoproxil fumarate would also be increased in the presence of a boosted PI. Substituting tenofovir alafenamide into that boosted PI regimen could have a significant impact on these current safety issues. Because many patients are dependent on a boosted PI due to resistance to other drug classes, in my opinion, the use of tenofovir alafenamide in this setting would have a substantial positive impact.
- ART, antiretroviral therapy; ATV, atazanavir; BID, twice daily; MOA, mechanism of action; QD, once daily; RAL, raltegravir; RTV; ritonavir; TDF, tenofovir. Joseph J. Eron, Jr., MD: For several years, the HIV field has lacked promising findings from new classes of drugs that function through novel mechanisms of action. At the HIV Drug Therapy meeting in Glasgow, Brinson and colleagues[23] reported on BMS-663068, a prodrug of the attachment inhibitor BMS-626529 that binds to the gp120 envelope protein of HIV-1 preventing viral attachment and subsequent host cell entry. Unlike CCR5 inhibitors, BMS-626529 is active against CCR5-tropic, CXCR4-tropic, and dual tropic viruses, although it should be noted that approximately 10% of patients are intrinsically less sensitive to this drug.[24,25] The current phase IIb study compared multiple BMS-663068 doses to atazanavir/ritonavir (both paired with raltegravir and tenofovir disoproxil fumarate) for 96 weeks in treatment-experienced patients with HIV-1 RNA ≥ 1000 copies/mL and CD4+ cell count &gt; 50 cells/mm3.[23] The trial enrolled approximately 50 patients per arm; all had demonstrated sensitivity to the active compound prior to enrolling in the study.
- AE, adverse event; ATV, atazanavir; BL, baseline; BID, twice daily; QD, once daily; RTV, ritonavir. Joseph J. Eron, Jr., MD: At 24 weeks, BMS-663068 demonstrated virologic activity comparable to atazanavir/ritonavir.[23] There is a suggestion that it may be slightly less active among patients with baseline HIV-1 RNA &gt; 100,000 copies/mL. However, interpreting the results from a 24-week endpoint presents a challenge because this data point does not provide information about the dynamics of virologic suppression over time. It is possible that this attachment inhibitor is similar to the PI class and it takes more time to achieve complete viral suppression. In this relatively small study of previously treated patients, BMS-663068 appears to have similar virologic activity to atazanavir/ritonavir when each is combined with raltegravir and tenofovir disoproxil fumarate. Adverse events were relatively uncommon in the BMS-663068 arms with only 4 patients discontinuing treatment because of adverse events and 4% to 8% of patients experiencing serious adverse events, depending on the dosing arm. Jürgen K. Rockstroh, MD: An important question raised by this study is how future clinical studies of BMS-663068 will be conducted as well as how this agent will fit into future clinical practice. The primary concern at this time is the requirement that patients be tested for sensitivity to the drug prior to trial enrollment and if sufficient numbers of patients can be identified to power future studies. Joseph J. Eron, Jr., MD: For a small number of patients in clinical practice, it would certainly be helpful to have a drug that works by a new mechanism. However, it is quite rare to have a patient for whom it is not possible to formulate a fully active regimen. Because this clinical scenario is uncommon, it was challenging to develop the clinical trial design. Based on the 0.7-1.5 log10 copies/mL mean HIV-1 RNA decrease during an 8-day functional monotherapy substudy involving 10 patients per BMS-663068 dosing arm, it is clear that this drug has antiviral activity in patients receiving a failing regimen. However, I agree that it is challenging to study this agent in the context of many other active drugs that do not require prescreening.
- AE, adverse event; ART, antiretroviral therapy; CNS, central nervous system; FTC, emtricitabine; QD, once daily; TDF, tenofovir. Jürgen K. Rockstroh, MD: The randomized, double-blind, dose-finding phase II Protocol 007 study evaluated doravirine plus tenofovir/emtricitabine in treatment-naive patients.[26] Part 1 of this trial compared doravirine administered at doses ranging from 25-200 mg once daily with efavirenz 600 mg once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate. Approximately 40 patients per arm were enrolled, all with HIV-1 RNA ≥ 1000 copies/mL and CD4+ cell counts ≥ 100 cells/mm3. Part 2 of the study compared doravirine 100 mg once daily with efavirenz 600 mg once daily, also each in combination with emtricitabine/tenofovir disoproxil fumarate, in 132 treatment-naive patients.
- DOR, doravirine; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate. Jürgen K. Rockstroh, MD: The virologic response rates at Week 48 of Part 1 were quite good across the different doravirine dosages for patients with baseline HIV-1 RNA ≤ 100,000 copies/mL.[26] In this subgroup, the proportion with HIV-1 RNA &lt; 40 copies/mL at Week 48 was numerically higher for all doravirine doses vs efavirenz. The same was true for the outcome of HIV-1 RNA &lt; 200 copies/mL at Week 48. Among patients with baseline HIV-1 RNA &gt; 100,000 copies/mL, the doravirine dose appeared to play a stronger role as rates of HIV-1 RNA &lt; 40 copies/mL were substantially lower at the lower doses. Based on these results, it appears that moving forward with the 100-mg dose of doravirine for Part 2 of the trial is well advised.
- FTC, emtricitabine; TDF, tenofovir. Jürgen K. Rockstroh, MD: The proportion of patients with virologic failure in Part 1 of the trial was comparable between the pooled doravirine dosing arms and the efavirenz arm.[26] Among patients with HIV-1 RNA ≥ 200 copies/mL at Week 48 who underwent resistance testing, NNRTI resistance was detected in 1 patient in the doravirine dosing arms vs 0 patients in the efavirenz arm; no NRTI mutations were detected in either arm. Overall, there was very little resistance in this study. The results of this trial are interesting and raise the question of whether another NNRTI is needed. If a newer NNRTI is at least as effective as efavirenz, lacks the central nervous system toxicity associated with efavirenz, and is available at a dosage that is low enough to allow coformulation, it may be an attractive option. Joseph J. Eron, Jr., MD: Researchers have been searching for the optimal NNRTI since the introduction of efavirenz, with the goal of attaining similar or better efficacy and avoiding some of the adverse central nervous system events. Rilpivirine initially appeared to fulfill those requirements but was then shown to have lower virologic efficacy at its current dose among patients with high HIV-1 RNA. In my opinion, doravirine has potential to fill this role. The virologic activity appears to be similar to efavirenz, and in a report from earlier in 2014, it appeared to have a lower rate of drug-related adverse events compared with efavirenz,[27] although a larger study will be required to confirm these findings. However, the current resistance analysis could be more inclusive as the investigators only performed resistance testing in patients with HIV-1 RNA &gt; 500 copies/mL, and frequently genotype results can be obtained in patients who have lower HIV-1 RNA on therapy.[26] As a result, there was a missed opportunity to interrogate in vivo resistance of doravirine more thoroughly in this study. Jürgen K. Rockstroh, MD: I suspect that when the 100-mg doravirine dose is evaluated in Part 2 of this trial, the likelihood of virologic failure may become even smaller. Joseph J. Eron, Jr., MD: I agree.
- HCV, hepatitis C virus.
- ATV, atazanavir; DAA, direct-acting antiviral agent; GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RAL, raltegravir; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. Jürgen K. Rockstroh, MD: The open-label phase II/III TURQUOISE-I study provides the first data on the use of paritaprevir/ritonavir/ombitasvir plus dasabuvir in patients coinfected with HIV and HCV. Patients with genotype 1 HCV infection and HIV infection received the 3-drug regimen plus ribavirin for 12 vs 24 weeks in this study (N = 63).[28] Paritaprevir is an HCV PI, ombitasvir is an HCV NS5A inhibitor, and dasabuvir is an HCV NS5B inhibitor. This combination was approved by the FDA in December 2014 for the treatment of genotype 1 HCV infection, when used with or without ribavirin depending on HCV subgenotype and cirrhosis status, and including patients with HIV coinfection.[29] The enrollment criteria for TURQUOISE-I required that patients be naive to previous treatment with an HCV direct-acting antiviral (DAA), but previous peginterferon and ribavirin therapy was permitted as was compensated cirrhosis.[28] Cirrhosis was present in 19% of the patient population and the majority of patients were HCV treatment naive (67%). Regarding HIV treatment status, patients were required to have HIV-1 RNA levels &lt; 40 copies/mL and CD4+ cell counts ≥ 200 cell/mm3 (or CD4+ ≥ 14%) on an atazanavir- or raltegravir-based antiretroviral regimen.
- HCV, hepatitis C virus; ITT, intent-to-treat; MSM, men who have sex with men; pegIFN, peginterferon; RAV, resistance associated variant; RBV, ribavirin; SVR, sustained virologic response; VF, virologic failure. Jürgen K. Rockstroh, MD: Overall, the SVR12 were an impressive 93.5% with 12 weeks of treatment vs 90.6% with 24 weeks of therapy, suggesting that there is no benefit to extending treatment from 12 to 24 weeks.[28] The finding that 12 weeks of therapy is sufficient has important implications for both financial and adherence reasons. When the 2 treatment durations were compared according to the antiretroviral regimen used, the SVR12 rates remained comparable between arms. It is worth noting that the FDA prescribing information indicates 24 weeks of treatment (in combination with ribavirin) be used for patients with genotype 1a HCV infection and cirrhosis, although there is a footnote that a 12-week duration can be considered according to previous treatment history.[29] For all other patients, 12 weeks is sufficient. The indicated regimens are the same for patients coinfected with HIV, underscoring that in the DAA combination era, success rates of HCV therapy are no longer different between HCV-monoinfected and HIV/HCV-coinfected patients. Therefore, modern DAA-based HCV therapy should not be withheld from HIV/HCV-coinfected patients in particular as they still remain at a higher overall risk for hepatic decompensation over time as compared with HCV-monoinfected patients. There are 2 important points that should be noted regarding virologic outcomes in this relatively small study. First, there were 2 cases of true virologic failure, both occurred in patients with genotype 1a HCV infection, previous null response to peginterferon and ribavirin therapy, and cirrhosis, and in both cases resistance associated variants were identified in all 3 HCV genes targeted by the triple DAA regimen.[28] Data from several trials indicate that patients with cirrhosis and previous null response to HCV therapy remain somewhat more difficult to treat, even with newer regimens. It is likely that different strategies will be needed for some patients in this subgroup. Second, although curing HCV infection is possible and is the goal of treatment, in patients who acquire HCV through intravenous drug use (ie, needle sharing) or, for HIV-infected men who have sex with men (MSM), through high-risk sexual behavior, the risk for reinfection remains high in the absence of behavior modification. In TURQUOISE-I, 2 HCV treatment–naive patients classified as experiencing posttreatment virologic failure without evidence of resistance associated variants likely reflect cases of HCV reinfection with a different isolate based on phylogenetic analysis.[28] Both patients identified themselves as MSM and reported high-risk sexual practices posttreatment. Therefore, it is vital that clinicians also counsel patients on behavior modification to limit the risk of reinfection after treatment. Joseph J. Eron, Jr., MD: I agree that this is an important study evaluating paritaprevir/ritonavir/ombitasvir plus dasabuvir and ribavirin in HIV/HCV-coinfected patients, and the results are quite favorable.[28] One concern with this regimen is that it requires ribavirin, which adds to both the regimen complexity as well as toxicity. The FDA-approved prescribing information for paritaprevir/ritonavir/ombitasvir plus dasabuvir indicates that ribavirin should be included in the regimen for all patients with genotype 1a HCV infection, the more challenging subtype for this particular regimen, and in patients with genotype 1b HCV infection who also have cirrhosis.[29] For patients who have genotype 1b HCV infection without cirrhosis, ribavirin is not indicated. As noted, the indicated regimens are the same for patients coinfected with HIV.
- AE, adverse event; ALT, alanine aminotransferase; ART, antiretroviral therapy; AST, aspartate aminotransferase; ATV, atazanavir; BID, twice daily; DAA, direct-acting antiviral; DRV, darunavir; EFV, efavirenz; FDC; fixed-dose combination; FTC, emtricitabine; GI, gastrointestinal; LPV, lopinavir; NA, not assessed; PK, pharmacokinetics; QAM; every day in the morning; QPM, every day in the evening; RAL, raltegravir; RBV, ribavirin; RPV, rilpivirine; RTV; ritonavir; TDF, tenofovir. Jürgen K. Rockstroh, MD: The latest European Association for the Study of the Liver HCV treatment guidance advises that there is no longer a difference in the treatment choice for patients with HCV monoinfection vs those with HIV/HCV coinfection, as virologic response rates in these 2 groups are comparable with currently recommended regimens.[39] This recommendation is very important because it will lead to easier access to therapies without necessarily requiring proof of efficacy in separate HIV/HCV coinfection trials. However, the guidance also highlights the considerable risk of drug–drug interactions between HCV therapy and antiretroviral therapy. Fortunately, Web-based resources are available for clinicians to check for any known drug interactions before initiating a particular HCV regimen in patients with HIV coinfection.[31-33] With the potential for these drug–drug interactions, it is important that investigators evaluate new and emerging DAAs in combination with antiretroviral agents. In one such analysis reported at ICAAC, Khatri and colleagues[34,35] evaluated drug–drug interactions between paritaprevir/ritonavir/ombitasvir plus dasabuvir and several commonly used antiretroviral agents in healthy volunteers. The data revealed the important finding that rilpivirine should not be coadministered with paritaprevir/ritonavir/ombitasvir and dasabuvir, as this increases the exposure of rilpivirine, which could increase the risk of QT prolongation.[34,35] This interaction is particularly noteworthy as rilpivirine did not have substantial drug–drug interactions with several previous HCV PIs. In addition, paritaprevir/ritonavir/ombitasvir and dasabuvir should not be coadministered with efavirenz/emtricitabine/tenofovir disoproxil fumarate or lopinavir/ritonavir because of increased toxicity. In the case of lopinavir/ritonavir coadministration, the daily ritonavir dose is higher than warranted because it is included in both the HCV and HIV fixed-dose combinations, and this leads to increased gastrointestinal toxicity. Joseph J. Eron, Jr., MD: I agree that the rilpivirine data are particularly important because rilpivirine has been safe to use with several other DAA-based HCV regimens. Therefore, it is important for physicians to be aware of the difference with this new regimen.
- CDC, Centers for Disease Control and Prevention; DC, District of Columbia; KP, Kaiser Permanente. Joseph J. Eron, Jr., MD: An issue that has been front and center for the last several years is how well patients are entered into and transit through the HIV care cascade. A group of investigators at Kaiser Permanente evaluated this cascade in the setting of their integrated healthcare system, which comprises more than 9 million members in 9 states and the District of Columbia, including more than 22,000 HIV-infected members in 2013.[36] The current analysis involved HIV-infected members 13 years of age or older. Investigators specifically evaluated whether age or sex had an impact on the care cascade in 2010-2012, in particular on linkage to care, retention in care, antiretroviral therapy prescription, and ultimately HIV-1 RNA suppression. Eighty-seven percent of the analysis cohort was male.
- ART, antiretroviral therapy. Joseph J. Eron, Jr., MD: Regarding sex differences, the results demonstrated that women were less likely than men to be linked to care, to fill an antiretroviral therapy prescription, and to achieve viral suppression in 2010 and 2011.[36] However, in 2012, there was no significant difference in these parameters between the sexes, perhaps suggesting that disparities in care are improving. Of interest, women had higher rates of retention in care than men in all study years. The analysis according to age group revealed that younger age was associated with lower rates of retention in care, antiretroviral therapy prescription, and viral suppression in all 3 study years.[36] Overall, this study shows that in a comprehensive healthcare system, HIV viral suppression rates of approximately 60% are attainable once HIV is diagnosed.[36] However, the challenges that clinicians face in the general population, including testing for infection, linking patients to care, and retaining patients in care, still remain. Jürgen K. Rockstroh, MD: Europe has also observed lower rates of HIV viral suppression in women, which is strongly affected by migrant populations, particularly from Africa, who have difficulties accessing social services and treatment. In the Kaiser Permanente study, the lower rates of prescription refill and HIV-1 RNA suppression in younger age groups highlight the need for potent and uncomplicated regimens in young people who have HIV.[36]