Начало АРТ впервые.Наилучшая практика.Best Practices in Antiretroviral Therapy-Initiating First-line Therapy. 2015
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Best Practices in Antiretroviral Therapy: Initiating First-line Therapy In this downloadable slideset, Charles B. Hicks, MD, discusses data on initiating antiretroviral therapy in HIV-infected patients. Format: Microsoft PowerPoint (.ppt) File size: 2.16 MB
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Начало АРТ впервые.Наилучшая практика.Best Practices in Antiretroviral Therapy-Initiating First-line Therapy. 2015
- 1. Best Practices in Antiretroviral Therapy: Initiating First-line Therapy This activity is supported by an independent educational grant from ViiV Healthcare
- 2. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Faculty Charles B. Hicks, MD Professor of Clinical Medicine Director, Owen Clinic University of California, San Diego San Diego, California Program Director Paul E. Sax, MD Clinical Director HIV Program and Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts
- 3. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Disclosures Charles B. Hicks, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and royalties from UpToDate, Inc. Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and funds for research support (paid to Brigham and Women’s Hospital) from Bristol- Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.
- 4. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line 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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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.
- 5. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Overview Initiating ART in patients with newly diagnosed HIV infection Initiating ART in HIV-infected patients with comorbidities Initiating ART in patients with advanced HIV infection
- 6. Initiating ART in Patients With Advanced HIV Infection
- 7. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts Immediate ART ART initiated immediately following randomization (n = 2326) INSIGHT START Study Group. N Engl J Med. 2015;[Epub ahead of print]. Lundgren J, et al. IAS 2015. Abstract MOSY0302. Deferred ART Deferred until CD4+ cell count ≤ 350 cells/mm3 , AIDS, or event requiring ART (n = 2359) HIV-positive, ART-naive adults with CD4+ cell count > 500 cells/mm3 (N = 4685) Study closed by DSMB following interim analysis
- 8. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Time on ART and ART Use Follow-up time on ART: – Immediate 94% – Deferred 28% Median time to ART initiation in deferred arm: – 3 yrs (IQR: 1.6-4.8; projected 4 yrs) ART use: – TDF: 89% in both arms – EFV: immediate 73% vs deferred 51% Immedi ate ART, % wi thHIV-1RNA≤ 200 c/mL Deferred ART, % using ART De fe rred ART, % with HIV-1 RNA ≤ 2 00 c/m L Immediate ART, % using ART INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. Mos Pts(%) 100 80 60 40 20 0 0 12 24 36 48 60 Time on ART
- 9. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Primary Outcome Primary Endpoint Immediate ART Deferred ART No. with event (%) 42 (1.8) 96 (4.1) Rate/100 PY 0.60 1.38 HR (immediate/deferred) 0.43 (95% CI: 0.30-0.62; P < .001) 57% reduced risk of serious events or death with immediate ART 68% of primary endpoints occurred in patients with CD4+ cell counts > 500 cells/mm3 10 8 6 4 2 0 CumulativePercent WithEvent 0 6 12 18 24 30 36 42 48 54 60 Mos INSIGHT START Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. 2.5 5.3 Immediate ART Deferred ART
- 10. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Serious AIDS Events 72% reduced risk of serious AIDS events with immediate ART INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. Serious AIDS Events Immediate ART Deferred ART No. with event (%) 14 50 Rate/100 PY 0.20 0.72 HR (immediate/deferred) 0.28 (95% CI: 0.15-0.50; P < .001) 0 6 12 18 24 30 36 42 48 54 60 Mos 10 8 6 4 2 0 CumulativePercent WithanEvent Immediate ART Deferred ART
- 11. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Serious Non-AIDS Events 39% reduced risk of serious non-AIDS events with immediate ART 0 6 12 18 24 30 36 42 48 54 60 Mos 10 8 6 4 2 0 CumulativePercent WithanEvent INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. Serious Non-AIDS Events Immediate ART Deferred ART No. with event (%) 29 47 Rate/100 PY 0.42 0.67 HR (immediate/deferred) 0.61 (95% CI: 0.38-0.97; P = .04) Immediate ART Deferred ART
- 12. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Types of Cancer *Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma. Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck. Cancer Event Immediate ART Deferred ART Kaposi’s sarcoma 1 11 Lymphoma, NHL + HL 3 10 Prostate cancer 2 3 Lung cancer 2 2 Anal cancer 1 2 Cervical or testis cancer 1 2 Other types* 4 9 Total 14 39 INSIGHT START Study Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
- 13. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START: Adverse Events No difference in risk of selected adverse events[1] TEMPRANO: immediate ART + 6 mos IPT reduced risk of severe illness vs deferred ART + no IPT in African pts with CD4+ > 500 cells/mm3[2] 1. INSIGHT START Group. N Engl J Med. 2015;373:195-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302. 2. TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015;[Epub ahead of print]. Other Secondary Endpoints[1] Immediate ART (n = 2326) Deferred ART (n = 2359) HR (95% CI) P Value n n/100 PY n n/100 PY Grade 4 event 73 1.06 73 1.05 1.01 (0.73-1.39) .97 Unscheduled hospitalization 262 4.02 287 4.40 0.91 (0.77-1.08) .28 Grade 4 event, unscheduled hospitalization, or death from any cause 283 4.36 311 4.78 0.91 (0.77-1.07) .25
- 14. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy START Substudy: BMD Changes With Immediate vs Deferred ART Over 3 Yrs Substudy included 192 pts in immediate ART arm and 204 pts in deferred ART arm Greater BMD loss in hip and spine with immediate vs deferred ART – Estimated mean difference for hip: -1.5% (95% CI: -2.3% to -0.8%; P < .001) – Estimated mean difference for spine: -1.6% (95% CI: -2.2% to -1.0%; P < .001) Osteoporosis and fracture incidence similar between arms Hoy JF, et al. EACS 2015. Abstract ADRLH-62. ChangeFromBL(%)ChangeFromBL(%) Total Hip BMD 0 -1 -2 -3 -4 -5 0 12 24 36 Immediate ART Deferred ART Total Spine BMD 0 -1 -2 -3 -4 -5 0 12 24 36 Mos From Randomization
- 15. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy HPTN 052: ART for Prevention of HIV Transmission in Serodiscordant Couples International, randomized, controlled trial ART offered to all index pts in delayed ART arm from May 2011 after interim results – 84% of pts in delayed ART arm had initiated ART at Yr 1 and 98% prior to study closure Stable, healthy, sexually active, HIV-discordant couples with CD4+ cell count 350-550 cells/mm3 (N = 1763 couples) Early ART Arm Initiate ART immediately (n = 886 couples) Delayed ART Arm Initiate ART at CD4+ count ≤ 250 cells/mm3 or at development of AIDS-defining illness (n = 877 couples) Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
- 16. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy HPTN 052: Reduced Risk of Partner Infection 8 linked HIV infections diagnosed after seropositive patient started ART – All occurred soon after initiation or after virologic failure No linked HIV transmissions observed when index participant stably suppressed on ART Partner Infections, n (rate/100 PY) Overall (April 2005 - May 2015) Early (4314 PY F/U) Delayed (4180 PY F/U) All 19 (0.44) 59 (1.41) Linked 3 (0.07) 43 (1.03) Risk Reduction With Early ART, % All infections 69 -- Linked infections 93 -- Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
- 17. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy DHHS and IAS-USA Guidelines: Recommended Regimens for First-line ART 1. DHHS Guidelines. April 2015. 2. Günthard HF, et al. JAMA. 2014;312:410-425. Class DHHS[1] IAS-USA[2] INSTI DTG/ABC/3TC* DTG + TDF/FTC EVG/COBI/TDF/FTC† EVG/COBI/TAF/FTC‡ RAL + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC† DTG + ABC/3TC*∫ DTG + TDF/FTC Boosted PI DRV + RTV + TDF/FTC ATV + RTV + TDF/FTC or ATV + RTV + ABC/3TC*§ DRV + RTV + TDF/FTC NNRTI EFV/TDF/FTC or EFV + ABC/3TC*§ or RPV/TDF/FTC§ *Only for pts who are HLA-B*5701 negative. Only for pts with pre-ART CrCl > 70 mL/min. ‡ Only for pts with pre-ART CrCl ≥ 30 mL/min. ∫ Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen. § Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL. Single-tablet regimens are in bold.
- 18. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy ACTG 5257: Open-Label ATV + RTV vs RAL vs DRV + RTV in First-line ART Primary endpoints – Virologic failure: time to HIV-1 RNA > 1000 copies/mL (at Wk 16 or before Wk 24) or > 200 copies/mL (at or after Wk 24) – Tolerability failure: time to discontinuation of randomized component for toxicity Composite endpoint: the earlier occurrence of either VF or TF in a given participant Switch of regimens allowed for tolerability Lennox JL, et al. Ann Intern Med. 2014;161:461-471. ART-naive pts with HIV-1 RNA ≥ 1000 copies/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 copies/mL, participation in metabolic substudy, CV risk DRV + RTV 800/100 mg QD + TDF/FTC (n = 601) Wk 96 after last patient enrolled
- 19. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy ACTG 5257: Primary Endpoint Analyses at Wk 96 Regimens equivalent in time to VF Lennox JL, et al. Ann Intern Med. 2014;161:461-471. Significantly greater incidence of treatment failure with ATV + RTV vs RAL or DRV + RTV – In part due to high frequency of hyperbilirubinemia* Considering both efficacy and tolerability, RAL superior to either boosted PI DRV + RTV superior to ATV + RTV Virologic Failure Tolerability Failure Composite Endpoint Difference in 96-Wk Cumulative Incidence (97.5% CI) 0-10 10 20 ATV + RTV vs RAL 3.4% (-0.7 to 7.4) DRV + RTV vs RAL 5.6% (1.3-9.9) ATV + RTV vs DRV + RTV -2.2% (-6.7 to 2.3) ATV + RTV vs DRV + RTV 9.2% (5.5-12.9) 0-10 10 20 ATV + RTV vs RAL 12.7% (9.4-16.1) DRV + RTV vs RAL 3.6% (1.4-5.8) Favors RAL Favors DRV + RTV 0-10 10 20 ATV + RTV vs RAL 14.9% (10.2-19.6) DRV + RTV vs RAL 7.5% (3.2-11.8) ATV + RTV vs DRV + RTV 7.5% (2.3-12.7) Favors RAL Favors DRV + RTV Favors RAL *Pts were allowed to switch regimens and remain on study.
- 20. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Study 103: EVG/COBI/TDF/FTC Noninferior to ATV + RTV + TDF/FTC Through Wk 144 Outcomes at Wk 144[3] EVG/COBI/ TDF/FTC ATV + RTV + TDF/FTC Treatment- related d/c, % 6 9 Virologic failure, % 8 7 Mean CD4+ cell count increase, cells/mm3 280 293 1. DeJesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-124. 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[1] Wk 144[3] 78 75 0 20 40 60 80 100 90 87 Δ: 3.1% (-3.2 to 9.4) 83 82 Wk 96[2]
- 21. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy International, randomized, double-blind phase III trial Pts generally well matched at baseline – Pts with HIV-1 RNA > 100,000 copies/mL: EVG/COBI/TDF/FTC arm 24%; ATV + RTV + TDF/FTC arm 25% WAVES: EVG/COBI/TDF/FTC vs ATV + RTV + TDF/FTC in Tx-Naive Women Squires K, et al. IAS 2015. Abstract MOLBPE08. EVG/COBI/TDF/FTC QD + Placebos for ATV, RTV, and TDF/FTC QD (n = 289) ATV + RTV + TDF/FTC QD + Placebo for EVG/COBI/TDF/FTC QD (n = 286) HIV-infected women with HIV-1 RNA ≥ 500 copies/mL; no previous ART; and eGFR ≥ 70 mL/min (N = 575) Wk 48 Open-label extension ATV 300 mg; RTV 100 mg; TDF/FTC 300/200 mg; EVG/COBI/TDF/FTC 150/150/300/200 mg
- 22. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy WAVES: EVG/COBI/FTC/TDF Superior to ATV + RTV + TDF/FTC At Wk 48 EVG/COBI/FTC/TDF superior to ATV + RTV + TDF/FTC – Overall treatment difference 6.5% (95% CI: 0.4%-12.6%) No significant differences between arms in change from BL for eGFR, spine or hip BMD, LDL or HDL cholesterol, total cholesterol to HDL ratio, or triglycerides Significantly greater increase in total cholesterol with EVG/COBI/ TDF/FTC Lower rate of discontinuations due to AEs with EVG/COBI/ TDF/FTC vs ATV + RTV + TDF/FTC (2.4% vs 7.0%) Squires K, et al. IAS 2015. Abstract MOLBPE08. Wk48HIV-1RNA<50c/mL(%) 100 80 60 40 20 0 Overall ≤ 100,000 > 100,000 HIV-1 RNA (copies/mL) EVG/COBI/TDF/FTC ATV + RTV + TDF/FTC 87 81 86 82 90 78 n = 289 286 220 214 69 72 Emergent Resistance EVG/COBI/FTC/TDF (n = 289) ATV+RTV + TDF/FTC (n = 286) Resistance analysis population 19 21 Developed resistance mutations to study drugs 0 3
- 23. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in Tx-Naive Pts Through Wk 144 Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV) Virologic Success* Virologic Nonresponse No Virologic Data Pts(%) Favors EFV/TDF/FTC 95% CI for Difference† 0% Wk 48 Wk 96 Wk 144 7.4% 8.0% 8.3% 2.5% 2.3 % 2% 14.6% 13.8% 12.3% Favors DTG+ABC/3TC 15% Pappa K, et al. ICAAC 2014. Abstract H-647a. 88 81 80 72 71 63 5 6 7 8 10 7 7 13 12 20 30 18 100 80 60 40 20 0 DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) Wk 48 96 144 Wk 48 96 144 Wk 48 96 144 *HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm. † -10% noninferiority margin. -5%
- 24. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy SPRING-2: DTG + NRTIs Noninferior to RAL + 2 NRTIs Through Wk 96 Outcomes at Wk 96[2] DTG + NRTIs RAL + NRTIs Treatment- related d/c, % 2 2 Virologic nonresponse, % 5 10 Mean CD4+ cell count increase, cells/mm3 276 264 HIV-1RNA<50copies/mL(%) 88 85 DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) 0 20 40 60 80 100 81 76 Wk 48[1] Wk 96[2] 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. Lancet Infect Dis. 2013;13:927-935. 361/ 411 351/ 411 332/ 411 314/ 411 Δ 4.5% (-1.1% to 10.0%) Δ 2.5% (-2.2% to 7.1%)
- 25. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy 40 FLAMINGO: DTG Superior to DRV + RTV in ART-Naive Pts Through Wk 96 Virologic Success Virologic Nonresponse No Virologic Data Favors DRV + RTV 95% CI for Difference 0%-12% Wk 48 Wk 96 Subjects(%) Favors DTG 25% DTG + 2 NRTIs (n = 242) DRV + RTV + 2 NRTIs (n = 242) Molina J-M, et al. HIV Drug Therapy Glasgow 2014. Abstract O153. 7.1% 12.4% 0.9% 4.7% 20.2% 13.2% Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96 100 80 60 20 0 83 90 80 68 6 7 8 12 4 10 12 21
- 26. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Studies 104/111: Tenofovir Alafenamide Fumarate vs TDF in Treatment-Naive Pts Parallel, randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA at Wk 48 TAF/FTC/EVG/COBI* single-tablet regimen (n = 866) TDF/FTC/EVG/COBI† single-tablet regimen (n = 867) Treatment-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL, eGFR ≥ 50 mL/min (N = 1733) Stratified by HIV-1 RNA, CD4+ cell count, geographic region Wk 48 Primary endpoint Wk 144 *10/200/150/150 mg once daily. † 300/200/150/150 mg once daily. Sax PE, et al. Lancet. 2015;385:2606-2615.
- 27. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Studies 104/111: TAF Noninferior to TDF at Week 48 TAF/FTC/EVG/COBI was noninferior to TDF/FTC/EVG/COBI at Wk 48 in each study: 93% vs 92% (Study 104); 92% vs 89% (Study 111) Declines in eGFR and in hip and spine BMD significantly less in TAF arm *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Sax PE, et al. Lancet. 2015;385:2606-2615. No Data Virologic Success* Virologic Failure Pts(%) 92 90 TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) 0 20 40 60 80 100 4 4 4 6 n = 800 784 Favors TAF 0 4.7%-0.7% 2.0% Treatment Difference (95% CI) -12% +12% Favors TDF Virologic Outcome
- 28. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Potential Advantages and Disadvantages of Single-Tablet Regimens Advantages Disadvantages Simplicity Convenience Fewer copays Reduces selective nonadherence to components of regimen Inability to adjust dosages of components if needed due to drug– drug interactions or tolerability issues, eg, renal insufficiency Not available for all ART regimens Not available for all NRTI pairings
- 29. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Available Single-Tablet Regimens Agent Type Yr of FDA Approval Efavirenz/tenofovir DF/ emtricitabine (EFV/TDF/FTC) NNRTI + dual NRTI 2006 Rilpivirine/tenofovir DF/ emtricitabine (RPV/TDF/FTC) NNRTI + dual NRTI 2011 Elvitegravir/cobicistat/ tenofovir DF/emtricitabine (EVG/COBI/TDF/FTC)* INSTI + booster + dual NRTI 2012 Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC)* INSTI + dual NRTI 2014 Elvitegravir/cobicistat/ tenofovir alafenamide/emtricitabine (EVG/COBI/TAF/FTC)* INSTI + booster + dual NRTI 2015 *DHHS recommended regimen for initial ART.
- 30. A 48-Year-Old Man With HIV Infection and Multiple Medical Problems
- 31. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Rising Rates of Comorbidities at HIV Diagnosis in USA Pts(%) Meyer N, et al. IAS 2015. Abstract MOPEB157. Medicare (> 65 Yrs) 100 80 60 40 20 0 All CV HTN DM Renal 2003 (n = 177; mean age 72.2 yrs) 2013 (n = 436; mean age 72.9 yrs) Pts(%) Medicaid 100 80 60 40 20 0 All CV HTN DM Renal 2003 (n = 3008; mean age 34.7 yrs) 2013 (n = 1632; mean age 39.2 yrs)
- 32. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy IAS-USA: Recommendations for Initial ART in the Settings of Specific Conditions In pts with or at high risk of CVD, consider avoiding ABC, LPV/RTV, or FPV + RTV In pts with reduced renal function, TDF should generally be avoided, especially with a boosted PI In pts at elevated fracture risk (eg, HCV coinfection, postmenopausal women, osteoporosis), it may be prudent to avoid TDF, especially with a boosted PI Günthard HF, et al. JAMA. 2014;312:410-425.
- 33. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy 1.80 1.60 1.40 1.20 1.00 0.00 D:A:D: Cumulative Exposure to ARVs Associated With Increased CKD Risk CKD Risk by Yrs of ARV Exposure, IRR (95% CI) Drug 1 Yr 2 Yrs 5 Yrs TDF 1.12 (1.06-1.18) 1.25 (1.12-1.39) 1.74 (1.33-2.27) ATV+ RTV 1.27 (1.18-1.36) 1.61 (1.40-1.84) 3.27 (2.32-4.61) LPV/ RTV 1.16 (1.10-1.22) 1.35 (1.21-1.50) 2.11 (1.62-2.75) Mocroft A, et al. CROI 2015. Abstract 142. Relationship Between Increasing Exposure to ARVS and CKD ATV+RTV LPV/RTVTDF On treatment TDF censored Univariate Multivariate
- 34. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy NA-ACCORD: Recent ABC Use and Risk of MI Several studies have reported an association between ABC use and MI risk; others found no association[2,3,4] 1. Palella F, et al. CROI 2015. Abstract 749LB. 2. Lundgren J, et al. CROI 2009. Abstract 44LB. 3. D:A:D Study Group. Lancet. 2008;371:1417-1426. 4. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 0 2.001.00 4.003.00 Full Study Restricted Study D:A:D Replication 1.95 1.33 Adjusted HRs for MI in Pts With Recent ABC Use[1] 7 clinical cohorts from NA-ACCORD (~ 20%) All ART users except pts on ABC at study entry ART-naive pts who initiated ART in the cohort
- 35. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Swiss HIV Cohort Study: Cumulative ABC Use and Risk of MI Continued exposure to ABC during past 4 yrs increased risk of a CVD event (HR: 2.06; 95% CI: 1.43 to 2.98) Young J, et al. J Acquir Immune Defic Syndr. 2015;69:413-421. Effect of Exposure to Abacavir On the Risk of CVD Events 0.04 0.03 0.02 0.01 0.00 -0.01 -0.02 Weight 0 Marginal structural Cox Conventional Cox 20 30 40 50 60 Time Elapsed Since Exposure to ABC (mos) 10 3.0 2.5 2.0 1.5 1.0 0.5 0.0HRofCumulative ExposuretoABC 0 Marginal structural Cox Conventional Cox 20 30 40 50 60 Length of Continuous Exposure to ABC (mos) 10
- 36. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Phase III Trial of EVG/COBI/TAF/FTC in Patients With CKD Multicenter, single-arm, phase III switch study Primary safety endpoint: eGFR at Wk 24 Baseline characteristics – Median age 58 yrs, median eGFR 56 mL/min, clinically significant albuminuria 49%, median CD4+ count 632 cells/mm3 , pre-switch TDF 65%, HTN 40%, DM 14% TAF/FTC/EVG/COBI (10/200/150/150 mg QD) single-tablet regimen HIV-infected pts with HIV-1 RNA < 50 copies/mL for ≥ 6 mos on ART, CD4+ cell count ≥ 50 cells/mm3 , and eGFR 30-69 mL/min (N = 242) Wk 24 Primary endpoint Wk 96 Gupta S, et al. IAS 2015. Abstract TUAB0103.
- 37. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Change in Renal Function Following Switch to EVG/COBI/TAF/FTC No change in actual GFR at Wk 48 In pts on TDF, tubular proteinuria improved after switch MedianChange FromBaseline eGFRCG mL/min eGFRCKD-EPI Cr mL/min/1.73m2 eGFRCKD-EPI cys C mL/min/1.73m2 TDF at BL Non-TDF at BLAll pts Baseline, n: 56 58 53 54 56 50 70 75 60 -0.6 +0.2 -1.8 -1.8* -1.5 -2.7* +1.6* -1.4 +2.7**P < .05 Gupta S, et al. IAS 2015. Abstract TUAB0103. Change in eGFR From Baseline to Wk 48 10 0 -10
- 38. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line 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;384:1942-1951. 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 in Proportion of Patients With Failure (RAL - TDF/FTC [95% CI]) -10 0 10 20 30 RAL TDF/FTC Adjusted Difference Estimate (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)
- 39. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy GARDEL: Dual Therapy Noninferior to Triple Therapy in Treatment-Naive Pts Pts(%) Treatment difference: +4.6% (95% CI: -2.2% to 11.8%; P = .171) Wk HIV-1 RNA < 50 copies/mL (ITTe) LPV/RTV + 3TC LPV/RTV + 3TC or FTC + NRTI 100 80 60 40 20 0 BL 4 8 12 24 36 48 88.3% 83.7% Cahn P, et al. Lancet Infect Dis. 2014;14:572-580.
- 40. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Recommendations on the Use of NRTI- Sparing Regimens in First-line ART Regimens using < 2 NRTIs should only be used in pts who cannot take ABC or TDF These regimens can be considered when ABC or TDF cannot be used: – DRV + RTV + RAL (only for pts with HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3 ) – LPV + RTV (BID) + 3TC (BID) DHHS Guidelines. April 2015
- 41. A 43-Year-Old Woman With An Opportunistic Infection
- 42. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Favors Deferred ART Zolopa AR, et al. PLoS ONE. 2009;4:e5575. ACTG 5164: Immediate vs Deferred ART In Pts With Acute Opportunistic Infections Risk of AIDS Progression/Death by Entry Diagnoses, OR (95% CI) Total PCP Bacterial infection Other OI Fungal Crypto Mycobacterial > 1 OI CD4+ < 50 CD4+ ≥ 50 Events, n 54 28 11 42 12 8 8 30 39 15 0 0.25 0.5 1.0 8.0 202.5 Log OR of Death/AIDS Progression Favors Early ART
- 43. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Prevalence of Drug Resistance Mutations in Treatment-Naive Patients, 2000-2013 Baseline plasma samples from 4 phase III trials (GS 903, 934, 104, 111; N = 2531) – 1617 samples analyzed for integrase mutations – 2531 analyzed for protease or RT mutations Substantial ↑ in prevalence of NNRTI resistance, modest ↑ in PI resistance Stable prevalence of NRTI resistance (mostly TAMs) – M184V/I ≤ 0.2%; K65R ≤ 0.2% Little evidence of transmitted INSTI resistance over period – Mostly T97A polymorphism 2000 (GS-903) 2003 (GS-934) 2013 (GS-104/GS- 111) 0 2 NNRTI 10 4 6 8 NRTI PI INSTI 0.5 1.0 0 4.2 8.7 3.2 2.6 2.6 1.2 2.4 2.9 1.4 Margot NA, et al. CROI 2014. Abstract 578.
- 44. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy FLAMINGO: Virologic Outcomes by Baseline HIV-1 RNA and NRTI Use Molina JM, et al. HIV Drug Therapy Glasgow 2014. Abstract O153. TDF/FTC (n = 325) ABC/3TC (n = 159) Baseline NRTI ≤ 100,000 (n = 362) > 100,000 (n = 122) Baseline HIV-1 RNA (c/mL) Pts With HIV-1 RNA < 50 c/mL at Wk 96 DTG + 2 NRTIs DRV + RTV + 2 NRTIs Overall (N = 484) Pts(%) 100 80 60 40 20 0 80 68 80 73 82 52 82 75 79 64
- 45. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Phase II Study of DRV/COBI/TAF/FTC vs DRV + COBI + TDF/FTC in Tx-Naive Pts Randomized, double-blinded, placebo-controlled trial Similar VL suppression at Wk 48 D/c for AEs: 2% (DRV/COBI/ TAF/FTC) vs 4% (DRV + COBI + TDF/FTC) No emergent resistance DRV/COBI/TAF/FTC associated with significantly greater increase in TC, LDL, HDL, and TG and with significantly less change in BMD at hip and spine Mills A, et al. J Acquir Immune Defic Syndr. 2015;69:439-445. Primary Endpoint: HIV-1 RNA < 50 c/mL at Wk 48 by FDA Snapshot Analysis (ITT) 100 80 60 40 20 0 W48W24 W48W24 W48W24 Virologic Success Virologic Failure No Data 8 45 2 16 12 24 20 84 777574 Weighted difference (95% Cl): Wk 24: 3.3 (-11.4 to 18.1) Wk 48: -6.2 (-19.9 to 7.4) DRV/COBI/TAF/FTC (n = 103) DRV + COBI + TDF/FTC (n = 50) Pts(%)
- 46. clinicaloptions.com/hiv Best Practices in Antiretroviral Therapy: Initiating First-line Therapy Summary Randomized trial data support ART initiation in pts with CD4+ cell count > 500 cells/mm3 ART guidelines recommend ART for all pts regardless of CD4+ cell count Recommended regimens for ART initiation have been revised ART selection should be individualized according to patient requirements, the evidence base, and practice guidance
- 47. Go Online for More CCO Educational Programming on Antiretroviral Therapy Downloadable PowerPoint slideset for use as a self-study resource or in your own presentations Additional CME-certified program on managing patients receiving antiretroviral therapy clinicaloptions.com/ARTStart
Editor's Notes
- Hello. I’d like to welcome you to today’s Clinical Care Options program entitled, “Best Practices in Antiretroviral Therapy: Initiating First-line Therapy.”
- This slide lists the faculty who were involved in the production of these slides.
- These are the disclosures for faculty involved in the development of this program.
- ART, antiretroviral therapy.
- ART, antiretroviral therapy; CVD, cardiovascular disease; DSMB, data and safety monitoring board; CVD, cardiovascular disease; ESRD, end-stage renal disease. The START trial was intended to answer the question: Is it appropriate to initiate antiretroviral therapy in persons with high CD4 counts, or is it safe to defer therapy until they achieve a point which may put them at greater risk for opportunistic infections and other HIV-associated complications? It was an international study with participants in 5 different continents. In order to enter the study, patients needed to have HIV infection and not previously to have been on antiretroviral therapy and to have a CD4 count greater than 500. They were randomized to either start antiretroviral therapy at the time of their entry into the study or to defer therapy until their CD4 count had fallen to less than 350. Now it’s important to know that at the time this study was designed, many guidelines for treatment in various countries had 350—or even 200—as the CD4 count where antiretroviral therapy was recommended. Over the period of enrollment, almost 5000 patients were actually enrolled and randomized in the study, and the outcome target was a combined endpoint of a patient either developing a serious AIDS event or dying from an AIDS-related condition or developing a serious non-AIDS event or dying from a disorder that was not attributable to the fact they were HIV positive, and those might include things like cardiovascular disease, serious cardiovascular disease, end-stage renal disease, liver decompensation, or non–AIDS-defining cancers.
- ART, antiretroviral therapy; IQR, interquartile range; TDF, tenofovir disoproxyl fumarate; EFV, efavirenz. Now this slide shows the time on antiretroviral therapy between the 2 groups and antiretroviral therapy use. And, obviously, the yellow/orange color is the immediate antiretroviral therapy, and you see early in the first month or two a high proportion of people start antiretroviral therapy, and a high proportion of people suppress HIV RNA. So of all the follow-up time in the study, 94% of that follow-up time patients in the immediate arm were on treatment, whereas the deferred arm didn’t start until their CD4 count dropped below the prespecified level, and so only 28% of the time that the trial was being conducted were persons randomized to that arm actually on therapy. The median time, if you were in the deferred arm, to starting antiretroviral therapy was about 3 years—it had been projected to be closer to 4 years—and the antiretrovirals that were selected, which could be any of the approved combination regimens—turned out to be almost 90% tenofovir-containing arms. In the immediate arm, 73% of persons started efavirenz, and just over half in the deferred arm, since in that setting many people started later when some of the practice patterns were evolving.
- ART, antiretroviral therapy. Now here’s the primary outcome. You can see that the increase in frequency of the events occurs more often in those deferring therapy compared to the population who started therapy early, such that the trial was actually stopped early because of an excess number of events occurring in persons on deferred therapy. You can see that at the time the study was stopped, just over 48 months after it started, there had been 42 events in those who started immediate therapy—or about 1.8% of the participants—compared to 96 events in the deferred antiretroviral therapy arm—4.1%—the rate per 100 patient-years of follow-up, 0.6 vs 1.38. And so overall there’s about a 57% reduction in the primary endpoint by starting antiretroviral therapy immediately compared to those who deferred.
- The one big question was would people with higher CD4 counts be at risk of developing AIDS-associated events, or would most of these be non-AIDS events? And what you can see from this slide is the difference between the 2 arms is mostly related to the occurrence of AIDS-associated events among those who deferred therapy.
- In contrast, here are the serious non-AIDS events. And although there are more in the deferred arm, the differences are much less dramatic than we saw with the AIDS-associated events; there’s a 39% reduced risk of serious non-AIDS event in the immediate arm compared to the deferred arm.
- Now what were the events? One of the important things was that cancer was a major difference. In the immediate therapy arm, there was a single case of Kaposi’s sarcoma; in the deferred therapy arm there were 11 cases. Similarly, there was a significant difference in lymphoma rates; this is particularly important, in more affluent parts of the world where some of the infection complications—primarily tuberculosis—is less common, but lymphoma remains a major problem. You can see that on deferred arm therapy, there were 10 lymphomas compared to 3 in those that were randomized to immediate antiretroviral therapy.
- Now one of the reasons for thinking that delaying therapy might have been a good idea was this notion that therapy was associated with adverse events, so they wanted to capture the adverse event rate because there was a concern that those who started therapy earlier would have excess adverse events compared to those with immediate therapy. But what you see in this slide is there’s absolutely no difference in the rate of grade 4 adverse events, in the rate of unscheduled hospitalizations, or in the combined endpoint of grade 4 event, unscheduled hospitalization, or death from any cause. So there does not appear to be any enhanced risk of adverse events among those who started antiretroviral therapy. Had there been that, it might have counterbalanced some of the primary outcome differences, but that was not the case. So I think the START trial convincingly demonstrates that initiating antiretroviral therapy after diagnosis is a critically important intervention irrespective of the initial CD4 count.
- ART, antiretroviral therapy; BL, baseline; BMD, bone mineral density; f/u, follow-up. Now included in part of the larger START study was the substudy looking at bone mineral density changes that occurred over 3 years in persons on the immediate or deferred antiretroviral therapy arms. There are almost 400 patients in total, including 192 in the immediate treatment arm and 204 in the deferred treatment arm. And what you can see from these 2 graphs is that the amount of bone mineral density loss was greater in the persons in the immediate arm, which may have reflected the combinations antiretroviral therapeutic agents that were used, but clearly that seems to be the case both in the hip and in the spine. I do think it illustrates also the point for us that HIV in and of itself seems to be associated with loss of bone mineral density, as was seen in both groups here. It’s important to note that end-organ outcomes, like fracture and also osteoporosis, really did not differ in instance between the 2 arms.
- ART, antiretroviral therapy. Now the other reason why this might be an important consideration—that is, starting antiretroviral therapy—has to do with preventing transmission. You may recall that the HPTN 052 study convincingly demonstrated that earlier initiation of antiretroviral therapy reduced the likelihood of transmission of HIV from an infected person to their sexual partner. After the 052 results became known, all the participants in the trial—those who started therapy initially and those who delayed therapy until they met the CD4 decline target—were offered antiretroviral therapy. And over time, almost 100% of them elected to start therapy; 84% in the delayed arm started therapy within the first year, and by the end of the study, study closure 4 years later, 98% were on treatment. The question was asked at the IAS meeting earlier in 2015: Did the difference in reduced numbers of transmissions carry over in the long term, and did it apply to the population that initially delayed antiretroviral therapy when they transitioned over to be on treatment?
- Now there were 8 linked HIV infections that occurred during this period and so there was some concern that maybe the longer-term efficacy of being on therapy wasn’t as good as had been seen in the initial presentation. However, closer examination of all 8 of these transmissions identified the fact that they occurred either very early after people started antiretroviral therapy before viral load had been suppressed or they occurred when patients were not taking their medicines consistently and had had virologic failure, and thus again, viruses around to be transmitted. There were no linked HIV transmissions that were seen when the index participant—the person with HIV—on suppressive antiretroviral therapy. This does not mean you can’t transmit the virus when you’re on antiretroviral therapy with a suppressed HIV RNA, but it does clearly indicate that the likelihood of transmission is dramatically decreased by being on suppressive antiretroviral 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; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load. EVG and DTG: Avoid simultaneous administration with antacids or other medications with divalent cations (Ca2+, Mg++, Al++, Fe++), as chelation of the integrase strand transfer inhibitor may reduce absorption. EFV: Efavirenz should be taken preferably at bedtime and on an empty stomach. ABC: Abacavir has been associated with an increased risk of cardiovascular complications; use caution in patients at high cardiovascular risk. Should only be administered to HLA-B*5701–negative patients. ABC/3TC: When administered with efavirenz or ritonavir-boosted atazanavir, abacavir/lamivudine was less efficacious with baseline HIV-1 RNA level &gt; 100 000 copies/mL vs tenofovir/emtricitabine. RPV: Rilpivirine should be taken with a full meal and should not be given with proton pump inhibitors. ATV and DRV: Atazanavir and darunavir should be taken with food. ATV: Avoid coadministration with H2-blockers or proton pump inhibitors or seek specific doses and dose separation schedules in the full prescribing information. RAL: Coadministration of raltegravir with aluminum and/or magnesium-containing antacids can reduce absorption of raltegravir and is not recommended. Raltegravir may be co-administered with calcium carbonate-containing antacids. Now let’s examine treatment guidelines as published by the Department of Health and Human Services, and the International Antiviral Society-USA. First on the left, let’s concentrate on the DHHS guidelines—improved outcomes data and longer-term follow-up have led to some revisions in recommended regimens in antiretroviral therapy. You’ll see that the single-tablet regimens are in bold—they consist of dolutegravir/abacavir/3TC or elvitegravir/cobicistat/tenofovir/FTC or the same combination in which TDF is replaced by tenofovir alafenamide. Those are integrase inhibitor–based regimen. There are 2 other integrase inhibitor–based regimens that are in the recommended group, dolutegravir plus tenofovir/FTC or raltegravir plus tenofovir/FTC and also darunavir/ritonavir plus tenofovir/FTC. Now the IAS-USA guidelines have a wider representation of classes, with integrase inhibitor obviously well represented, but also more options in the recommended group that are based on ritonavir-boosted protease inhibitors, and also nonnucleoside reverse transcriptase inhibitors, with some qualifications based on the patients that are being considered for therapy.
- 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. Now what information underlies these current guidelines? I think one of the most important ones is the AIDS Clinical Trials Group 5257 study, which was an open-label trial in 1800 patients comparing initial therapy using atazanavir/ritonavir vs darunavir/ritonavir, or using the integrase inhibitor raltegravir-based therapy. You can see that the 3 treatment arms are shown here. Just over 600 patients were randomized to each of the different arms, and all of the drugs that were given were also administered with the fixed-dose combination tenofovir/FTC. Now interestingly in this study, if someone was intolerant of the regimen, then that was considered as a endpoint, but there was also analysis of the outcomes with a switch of regimens aside from the main study drug due to tolerability, and there was a composite endpoint which was either occurrence of viral failure or treatment failure; that is, patients weren’t taking the regimen in a given participant.
- ATV, atazanavir; DRV, darunavir; RAL, raltegravir; RTV, ritonavir; VF, virologic failure. Well, let’s look at the results of ACTG 5257. This is obviously a very important study, and it’s rather complex and the results are a bit difficult to go through the details of, but I think the messages at the end are important and I think they’re well supported by the data that’s available. The first comparison is the time to virologic failure. And there was really no significant difference in the time to virologic failure among the 3 arms. The second category was tolerability failure. And in this comparison, the atazanavir arm fared poorly in large measure because of a high frequency of hyperbilirubinemia that led to investigators discontinuing therapy, as per the protocol. And as a consequence of this, and other side effects, there was a significantly greater incidence of tolerability treatment failure with the atazanavir/ritonavir arm compared to either the other protease inhibitor, darunavir/ritonavir, or to raltegravir. If we combine this now, both virologic failure and tolerability failure, we get the composite endpoint. And I think this is the richest part of the data that we want to kind of take to the bank here. If we consider both then efficacy and tolerability, and we compare them vs one another, the raltegravir arm—the integrase inhibitor arm—is superior; it’s superior to either of the boosted PIs. And, remember, this is the only arm in which the therapy had to be taken twice daily; both of the protease inhibitors were given in a once-daily regimen. So even with the twice-daily necessity, the raltegravir arm was superior to either of the protease inhibitors. If you compare the protease inhibitors one to the other, the darunavir/ritonavir arm was superior to atazanavir/ritonavir. Now, I think the ultimate outcome here was very influential in the evolution of the guidelines by bringing integrase inhibitors to the fore among the recommended regimens; in fact, for atazanavir, taking it off the list of recommended combinations, leaving only darunavir/ritonavir as one of the recommended combinations, the only protease inhibitor. So this is an important study and I think it’s really shaped the treatment recommendations in the couple of years that have lapsed since the study was first presented.
- ATV, atazanavir; BL, baseline; CI, confidence interval; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. There have been other studies, as well, establishing the value of integrase inhibitors in initial therapy. The 103 study compared the fixed-dose combination of elvitegravir/cobicistat/tenofovir and FTC to a PI regimen atazanavir/ritonavir plus tenofovir/FTC, and showed that the integrase inhibitor arm was not inferior to the PI-based arm. In fact, as you can see here, in virtually every category was numerically superior in terms of the proportion with viral load less than 50 copies, but by the statistical analysis it was not inferior.
- ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; QD, once daily; RTV, ritonavir. A more recent presentation from the International AIDS Society meeting in Vancouver in 2015 was the WAVES study, which was the largest study involving women only of initiation of antiretroviral therapy. This was conducted in response to an FDA review of the initial drug application in which it was noted that insufficient numbers of women had been studied, and the company was tasked with doing a study that included more women, and, hence, the WAVES study was done. This was an international, randomized, double-blind phase III trial comparing atazanavir/ritonavir/tenofovir/FTC to the fixed-dose combination elvitegravir/cobicistat/tenofovir/FTC; there were about 280-290 patients in each arm, the proportion of patients with higher viral loads were similar, and the characteristics of the patients appeared to be comparable in the 2 arms. It involved only women whose pretreatment viral load was above 500 who’d not been on antiretroviral therapy before and who had an estimated glomerular filtration rate greater than 70 because they were all getting tenofovir.
- AE, adverse event; ATV, atazanavir; BL, baseline; BMD, bone mineral density; COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; TDF, tenofovir disoproxil fumarate; RTV, ritonavir. The next slide shows the outcomes data and shows that there was a fairly convincing superiority of the elvitegravir/cobicistat arm over the atazanavir/ritonavir arm, which is shown in the bar graph here. And this difference was particularly notable for patients with higher viral loads, with a 90% response rate to the integrase inhibitor arm, a 78% response rate in the atazanavir-containing arms. There were also fewer discontinuations related to adverse events in the integrase inhibitor arm. So this trial shows that in women, integrase inhibitor–based therapy with elvitegravir appeared to be better than a protease inhibitor regimen that’s often proposed for women because it is among the potentially recommended therapies in pregnancy, atazanavir/ritonavir.
- Now in addition, there’s data on dolutegravir. The SINGLE study looked at dolutegravir plus the nucleoside combination abacavir/3TC and compared it to the 1-pill-daily combination of efavirenz/tenofovir/FTC and showed that the dolutegravir-based regimen was actually superior in treatment-naive patients, now followed out for a period of 3 years. There was also, importantly, no resistance that appeared to emerge in the 39 patients with dolutegravir who had treatment failure compared to 7 out of 33 patients on efavirenz who had treatment failure. So you can see on the point estimates, as well as the 95% confidence interval chart on the right-hand side of this slide, that the Week 48, Week 96, and Week 144 outcomes were consistently favoring the dolutegravir/abacavir/3TC arm.
- 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; QD, once daily; TDF, tenofovir. The SPRING-2 trial compared dolutegravir plus nucleosides—either abacavir/3TC or tenofovir/FTC—to raltegravir plus 2 nucleosides through Week 96, and you can see that the dolutegravir plus nucleosides arm was not inferior to the raltegravir arm. While the dolutegravir arm was numerically superior, statistically one can only say that dolutegravir plus nucleosides was not inferior to raltegravir plus nucleosides.
- And, finally, the FLAMINGO trial compared dolutegravir to the favored protease inhibitor–based regimen of darunavir/ritonavir; this slide showing the 96-week data in antiretroviral-naive patients and clearly showing that those randomized to receive dolutegravir plus 2 nucleosides had an increased proportion with suppressed viral load compared to those on darunavir/ritonavir plus 2 nucleosides.
- COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. It’s worth taking a few moments to look at some of the data on tenofovir alafenamide. This version of tenofovir is intended to replace the one we’ve used for a long time, which is TDF, as part of combination treatment regimens based on the notion that the tenofovir alafenamide version will be efficacious but will have decreased toxicity and adverse events. So here are studies looking at that question, here comparing the standard version of tenofovir/FTC/elvitegravir and cobicistat to the same combination in which TDF is replaced by tenofovir alafenamide. And outcome data for the primary endpoint is the 48-week proportion that have viral load less than 50 copies.
- AE, adverse event; COBI, cobicistat; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TAF, tenofovir alafenamide fumarate; tenofovir disoproxil fumarate; VF, virologic failure. This slide shows that data. You can see that virologic success occurred in 92% of those on tenofovir alafenamide, and 90% of those on TDF. There was no difference in virologic failure, and there was missing data on 4% or 6%, respectively. And you’ll note that again on the right, the point estimate showed 2% improved outcome in the tenofovir alafenamide arm, but the 95% confidence intervals cross 0, so therefore one concludes that tenofovir alafenamide was not inferior to TDF at Week 48. The issue of whether or not this version of tenofovir has diminished toxicity was addressed by looking at bone mineral density and showing that the change in bone mineral density was significantly less with tenofovir alafenamide compared to TDF. This was also reflected in the degree of estimated glomerular filtration rate decline, which was higher in the TDF vs the tenofovir alafenamide arm.
- Clearly, single-pill combinations are simpler. They’re convenient. Generally, there’s only a single copay. And selective nonadherence, where people take some of the treatment regimen but not all of it, is not possible when you have a single-pill regimen. In contrast, there may be some disadvantages. If there’s toxicity associated with one of the drugs in the combination, you clearly can’t adjust the dosage since they’re all fixed in the single tablet, and therefore adjusting the regimen based on tolerability or adverse event profiles cannot be done. Similarly, there may be some combinations that are particularly attractive for particular patients, and obviously they’re not all packaged into single-pill combinations, and that’s true not only for the third drug, but also for the nucleoside combinations that are commonly used in antiretroviral therapy.
- Well, what are our single-pill combinations that are available as of 2015? Well, the earliest one, as all of you know, was efavirenz/tenofovir/emtricitabine. This was actually approved almost 9, well fully 9 years ago, it’s been around through 2000 since 2006; it’s been really a workhorse for many years. But as with most drugs, their lifecycle 9 years into availability, it’s often been supplanted by newer agents that address some of the shortcomings of the earlier agents, and clearly efavirenz has some tolerability issues, some lipid issues, and some long-term side effect issues that have led to newer combinations being released. Five years later in 2011, rilpivirine—another nonnucleoside reverse transcriptase inhibitor—entered the market with the same pairing of tenofovir/FTC. Unfortunately, the dose of rilpivirine in this combination is limited due to potential toxicity, so while the drug works okay, it’s only approved for use in patients with baseline viral loads of less than 100,000. It also has issues with needing food to be properly absorbed, and it can’t be taken with proton pump inhibitors. So while it’s a useful drug, I think it’s kind of a niche drug that only has a certain proportion of patients for whom it is appropriate. Now the following year in 2012, we got the first integrase inhibitor fixed-dose combination, and that’s elvitegravir/cobicistat/tenofovir and emtricitabine. And this drug was very popular and has been used extensively, I think it’s really been quite excellent. The only reservation I have with this one is it does require a booster, and all things being equal I’d be just as happy not to have someone on a booster. But that booster here doesn’t usually interfere much, and this is a really potent combination, and we’ve liked it a lot. But just to take a quick jump down to the last line, most recently of all the combination pills, elvitegravir/cobicistat/emtricitabine now with tenofovir alafenamide has become available. And the tenofovir alafenamide was introduced to try and deal with some of the shortcomings of tenofovir disoproxil fumarate, primarily the potential for renal injury and for bone mineral density problems. It appears to do this, although I would hasten to add we’re pretty much in the early days; I don’t think we necessarily know all the things that might occur over the longer terms, but I do think this is a step forward and this, I’m sure, will be quite a popular combination. It does also have the booster, as noted. And, finally in 2014, dolutegravir/abacavir/lamivudine was introduced, also an integrase inhibitor–based compound; no booster required. But compared to the others, it’s paired with abacavir/lamivudine which introduces some issues potentially; cardiac risk factors and abacavir hypersensitivity syndrome. And so there are some shortcomings there as well, but dolutegravir is a terrific drug. Any of these combinations are really highly likely to be efficacious, but I think tailoring them to an individual patient’s circumstances, you should be able to get a good outcome with a single-pill combination.
- Now, the first thing to appreciate is this case with several comorbidities is not trivial and not uncommon. As our patient population in the HIV clinic ages, approaching now a median age of 50 among all HIV-infected patients in the United States, not surprisingly the rate of comorbidities in our HIV-infected patients is also rising. If you look at the Medicare data, the proportion with comorbidities among those age 65 or greater are shown in this slide—cardiovascular comorbidity at around 20%, hypertension in more than 60%, diabetes in over 50%, and some renal dysfunction in more than a quarter when you look at the 2013 data. And if we look at the Medicaid database overall, again you see there’s some increased risk of hypertension as a comorbidity, diabetes and renal disease, although the overall rates of those comorbidities are less in the Medicaid than in the Medicare population, obviously reflecting the age differences in the groups.
- Now, if we now look, at the IAS-USA recommendations for initial antiretroviral therapy, in the setting in which some of these conditions are present, we can note the following: In patients who are at high risk of cardiovascular disease, or who have already diagnosed cardiovascular disease, consideration should be given to avoiding drugs that epidemiologically have been linked to higher likelihood of cardiovascular disease, including abacavir, lopinavir/ritonavir, or fosamprenavir plus ritonavir. The second point is in patients with reduced renal function, TDF should generally be avoided, especially when it’s given with a boosted protease inhibitor, which tends to raise the exposure to tenofovir in that patient. And, finally, in patients with increased risk of bone fracture—for example, those who have hepatitis C coinfection, in postmenopausal women, in those with diagnosed osteoporosis—it may be prudent to avoid TDF, especially again with a boosted PI where the TDF exposures are increased.
- Well, let’s look at some of the data behind these recommendations. First, the D:A:D study which has looked at the question of cumulative exposure to antiretrovirals and the risk of increased chronic kidney disease. And you can see that the 3 drugs that this seemed to be relevant for were tenofovir disoproxil fumarate—or TDF—atazanavir/ritonavir, and lopinavir/ritonavir, as was noted in the earlier slide showing those drugs may, in fact, be an issue in those with some level of renal insufficiency. And you can see the degree of concern seems to be greatest for the atazanavir/ritonavir combination, followed by lopinavir/ritonavir, followed by the TDF.
- ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MI, myocardial infarction. The NA-ACCORD study addressed a previous finding of the D:A:D study regarding current or recent abacavir use and the risk of coronary artery disease or myocardial infarction. In this study, the population was those who were on or had recently been on abacavir, the vertical dotted line represents a hazard ratio that’s the same as all the people not on abacavir, and the area to the right represents the degree of increased risk as regards having a myocardial infarction that’s associated with being on abacavir. In the 7 clinical cohorts in NA-ACCORD that were included in this analysis, you can see that using the D:A:D methodology, the use of abacavir appeared to confer increased risk of coronary artery disease at a degree that was almost the same as that which had been previously reported in D:A:D. If one looks at the full study of all antiretroviral users except patients who were already on abacavir at the time of study entry, then that risk seems to be attenuated down to 1.33, and, in fact, this did not appear to be a significantly different hazard ratio compared to those not on abacavir. And, finally, if you take then the people who entered the analysis not on antiretroviral therapy and who initiated therapy during the cohort, then the use of abacavir also was associated with a higher rate of coronary artery disease. In fairness, there are other studies that have looked at that linkage between abacavir and MI risk and found no association, so there is some difference of opinion.
- Further information on this comes from the Swiss HIV Cohort study, which looks at cumulative abacavir use and the risk of myocardial infarction and appears to show that continued exposure to abacavir in the previous 4 years prior to the time of analysis increased the risk of cardiovascular event, with a hazard ratio of about 2, and the 95% confidence interval did not include one, so this appeared to be a statistically significant association between cumulative abacavir use and the risk of myocardial infarction. Now so that’s the information that underlies the notion that persons who have been diagnosed with coronary artery disease or appear to be at high risk should probably avoid abacavir.
- Well, a phase III switch trial of elvitegravir/cobicistat/tenofovir alafenamide and FTC—so this is the newer version of tenofovir—in patients with chronic kidney disease was recently presented at the IAS meeting earlier in 2015. These were patients that had a GFR between 30 and 69 in order to get into the study. As it turned out, almost all of them had sort of higher GFRs, the median being 56. But half of them had significant albuminuria, and 40% had hypertension, 14% diabetes, and two thirds of them were already on tenofovir at the time of the switch from the standard version of tenofovir to tenofovir alafenamide. The primary safety endpoint was change in GFR at Week 24 after starting this tenofovir alafenamide–containing regimen.
- So this slide shows the change in renal function after the switch, and what you note is there really isn’t much of any change in renal function over that first 48 weeks of observation. Not shown is the fact that there is a significant decline in tubular proteinuria in patients on tenofovir at the time of the switch, but it’s harder to identify that there’s a meaningful switch in GFR over the period of observation.
- BL, baseline; DRV, darunavir; FTC, emtricitabine; PDVF, protocol-defined virologic failure; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. Well let’s look at the results of the NEAT study here, again, comparing either tenofovir/FTC plus boosted darunavir or raltegravir plus boosted darunavir; the raltegravir arm, obviously, being the nuc-sparing combination. Overall in the NEAT study, the primary endpoint Week 96 the difference in the proportion of patients with treatment failure the raltegravir, darunavir/ritonavir arm was not inferior to the tenofovir/FTC, darunavir/ritonavir arm. That’s in the overall population; that’s also true for persons with viral loads less than 100,000 and/or CD4 counts greater than 200. But if you stratify by CD4 count above and below 200 and viral load above and below 100,000, you see something different. In the population whose baseline viral load was greater than 100,000, the tenofovir/FTC, darunavir/ritonavir arm pretty much outperformed the raltegravir, darunavir/ritonavir arm. And similarly for those with CD4 counts below 200, the tenofovir/FTC, boosted darunavir arm outperformed the raltegravir, nucleoside-sparing darunavir/ritonavir arm. So at the higher viral loads/lower CD4 counts, the 2 nucs plus protease inhibitor was better than the nuc-sparing integrase plus protease inhibitor. And I think we need to think about this when we’re considering whether or not this is an appropriate regimen for patients for whom we have concerns about trying to use the nucleosides.
- BL, baseline; DT, dual therapy; ITTe, intent-to-treat exposed population; TT, triple therapy; VL, viral load. Another study that looked at not using abacavir/tenofovir was the GARDEL study. This trial looked at dual therapy using the protease inhibitor lopinavir/ritonavir plus lamivudine/3TC or a more standard combination in which lopinavir/ritonavir was given with 3TC or FTC plus another nucleoside. And here you see that the proportion of patients with suppressed viral load less than 50 copies at Week 48 was slightly better in the arm in which lopinavir/ritonavir/3TC was used compared to those who got the more standard 2 nucleosides plus lopinavir/ritonavir, although the confidence interval for the point estimate included 0. Hence the conclusion is that the arms were noninferior to one another, but neither was superior to the other.
- So what are the recommendations on the use of so-called nuc-sparing regimens in first-line antiretroviral therapy? Well, the April 2015 version of the DHHS guidelines includes the following: Regimens with fewer than 2 nucleosides should only be used in patients who cannot take abacavir or tenofovir. And these regimens can be considered when abacavir or tenofovir cannot be used, and the ones that are listed are based on those clinical trials results we’ve discussed: darunavir/ritonavir plus raltegravir, with the caveat that this is proposed only for patients with a viral load less than 100,000 and a CD4 count greater than 200, and lopinavir/ritonavir plus 3TC given twice daily was also recommended as a possibility.
- The most relevant study is one that was published in 2009, the AIDS Clinical Trials Group 5164 study where persons with a thoroughly documented diagnosis of various opportunistic infections were randomized to either start therapy immediately or to defer therapy to a follow-up visit after the acute hospitalization was over. And you can see that clearly the data favors early antiretroviral therapy, for bacterial infections, other opportunistic infections, fungal disease. The point estimate is consistently in favor of early antiretroviral therapy, but because the number of events is small in many instances, the confidence intervals do not cross 1, and therefore we can’t be certain that early intervention necessarily is better, but there’s no question that the trend, no matter how you examine this, favors early initiation of therapy. And I think there’s broad agreement now that that, in fact, is probably the preferred strategy.
- BL, baseline; PI, protease inhibitor; RT, reverse transcriptase; TAM, thymidine analogue mutation. Well, the first thing is we’re going to recommend potentially starting her on therapy before we have the results of our resistance test. Here’s data that was presented in 2014 on the Conference on Retroviruses and Opportunistic Infection, and it shows prevalence of resistance mutations during the period 2000- 2013. It in particular highlights the increase in detected resistance over the time frame examined, most notably with a significant increase in NNRTI resistance, usually the K103 mutation. Mutations that seem to have a higher fitness cost, like M184V or K65R, were very uncommon, occurring in only 0.2% of instances. And perhaps even more interesting was the almost complete lack of transmitted resistance to integrase inhibitors; the data shown here suggests it could be as high as 1.4%, but other recently compiled data show that the likelihood of transmitted integrase resistance is vanishingly low, at least so far.
- The FLAMINGO trial compared efficacy with dolutegravir plus 2 nucs to that of darunavir/ritonavir and 2 nucs in treatment-naive patients. And what you’ll note here is that the proportion of patients with suppressed viral load less than 50 at Week 96 was clearly better with dolutegravir than with boosted darunavir.
- BMD, bone mineral density; COBI, cobicistat; Cr, creatinine; DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; ITT, intent to treat; LDL, low density lipoprotein; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir DF; TG, triglycerides. A phase II study of darunavir/cobicistat and tenofovir alafenamide FTC—the new version of tenofovir—compared to darunavir/cobicistat/tenofovir/FTC also appeared to show that there was no significant difference between the 2 arms. One was noninferior to the other, although you’ll note that the point estimate suggests that perhaps the virologic success rates at Week 48 were better with the darunavir/cobicistat plus tenofovir/FTC than the tenofovir alafenamide arm, although again not statistically significant. Interestingly, darunavir/cobicistat/TAF/FTC was associated with higher increases in total cholesterol, LDL, HDL, and triglycerides, probably because the actual exposure to tenofovir was less, and tenofovir has been demonstrated to be a lipid-lowering agent. At the same time, the lowered exposure translated into less change in bone mineral density at the hip and spine. So the tenofovir alafenamide version of this combination appears like it may, in fact, be a good option moving forward.
- Well, in summary, randomized clinical trial data support antiretroviral initiation in patients, irrespective of CD4 count, changing our prior approach which said that those with the highest CD4 counts could safely defer therapy until their T cells dropped below 500. And now antiretroviral guidelines consistently recommend antiretroviral therapy for all patients, irrespective of CD4 count. These guidelines will increasingly be adopted worldwide as well. Improved outcomes data and longer-term follow-up have led to some revisions in recommended regimens in antiretroviral therapy, as we have discussed, and these may continue to change as new drugs become available. The most important factor is that antiretroviral selection needs to be individualized according to the patient’s preferences, needs, the evidence that’s available, and all of the other factors that go into individualizing antiretroviral therapy for a particular patient.