Integrating Recent Data When Selecting First-line Antiretroviral Therapy This activity is supported by an educational grant from Merck.

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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 W. David Hardy, MD Clinical Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California 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 This slide lists the faculty who were involved in the production of these slides.

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 AbbVie and GlaxoSmithKline/ViiV. W. David Hardy, MD, has disclosed that he has received consulting fees from Gilead Sciences, GlaxoSmithKline/ViiV, and Janssen; has received funds for research support from Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Vertex; and has ownership interest (stocks, stock options or other ownership interest) in Merck. 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. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Overview of First-line Antiretroviral Therapy

Regardless of BL VL or CD4+ Count DHHS and IAS-USA Guidelines: 2014 Recommended Regimens for First-line ART Class DHHS[1] IAS-USA[2] Regardless of BL VL or CD4+ Count Pts With Pre-ART VL < 100,000 c/mL NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC EFV/TDF/FTC or EFV + ABC/3TC*‡ or RPV/TDF/FTC‡ Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC ATV/RTV + ABC/3TC* ATV/RTV + TDF/FTC or ATV/RTV + ABC/3TC*‡ INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC║ DTG + ABC/3TC*§ DTG + TDF/FTC 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS, International Antiviral Society; 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 > 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. *Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL. ║Only for pts with pre-ART CrCl > 70 mL/min. §Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen. 1. DHHS Guidelines. May 2014. 2. Günthard HF, et al. JAMA. 2014;312:410-425.

DHHS Guidelines: 2015 Recommended Regimens for First-line ART Class DHHS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC† DTG + TDF/FTC Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC*† DRV/COBI + TDF/FTC* NNRTI EFV/TDF/FTC RPV/TDF/FTC‡ 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load *Only for pts with pre-ART CrCl ≥ 70 mL/min. †Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3. DHHS Guidelines. April 2015.

Selecting Initial Antiretroviral Therapy

Selected Drug–Drug Interactions of INSTIs Agent Potential Drug–Drug Interactions Raltegravir[1] Metabolized by UGT1A ATV increases RAL concentrations; dose adjustment not recommended Avoid aluminum- and/or magnesium-containing antacids Rifampin decreases RAL levels; double RAL dose if coadministered with rifampin Elvitegravir/ cobicistat[2] Metabolized by CYP3A, CYP2D6 COBI increases levels of drugs metabolized by CYP3A Separate dosing with aluminum- and/or magnesium-containing antacids Not recommended for use with rifamycins Dolutegravir[3] Metabolized by UGT1A, with contribution from CYP3A Avoid use with ETR unless coadministered with boosted PI; avoid dosing with NVP DTG may increase metformin concentrations; metformin dose adjustment may be needed; monitor clinically when starting or stopping DTG ATV, atazanavir; COBI, cobicistat; DTG, dolutegravir; ETR, etravirine; NVP, nevirapine; RAL, raltegravir. 1. Raltegravir [package insert]. 2. EVG/COBI/TDF/FTC [package insert]. 3. Dolutegravir [package insert].

DHHS Guidelines, April 2015: What to Start Alternative Regimens NNRTI based EFV/TDF/FTC RPV/TDF/FTC* PI based ATV/COBI + TDF/FTC† ATV/r + TDF/FTC DRV/COBI + ABC/3TC‡ DRV/r + ABC/3TC‡ DRV/COBI + TDF/FTC† *Only for pts with pre-ART HIV RNA < 100,000 copies/mL and CD4 > 200 cells mm3. †Only for pts with pre-ART CrCl ≥ 70 mL/min. ‡Only for pts who are HLA-B*5701 negative. 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir. An alternative regimen may be the preferred regimen for some pts DHHS Guidelines. April 2015.

The International Antiviral Society–USA Recommended Treatment Regimens Class IAS-USA[1] NNRTI EFV/TDF/FTC or EFV + ABC/3TC*† RPV/TDF/FTC† Boosted PI ATV/RTV + TDF/FTC or ATV/RTV + ABC/3TC*† DRV/RTV + TDF/FTC INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC‡ DTG + ABC/3TC*§ DTG + TDF/FTC 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; IAS, International Antiviral Society; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; WHO, World Health Organization. *Only for pts who are HLA-B*5701 negative. Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL. ‡Only for pts with pre-ART CrCl ≥ 70 mL/min. §Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen. Currently preferred WHO regimens: EFV/TDF/FTC or EFV/TDF/3TC due to efficacy and cost of treatment[2] 1. Günthard HF, et al. JAMA. 2014;312:410-425. 2. WHO. The strategic use of antiretrovirals to help end the HIV epidemic. 2012.

Comparing Integrase Inhibitor Regimens

FLAMINGO: Wk 96 Subgroup Efficacy Analysis DTG + NRTIs (n = 242) DRV/RTV + NRTIs (n = 242) 100 82 82 80 80 79 80 73 75 68 64 60 52 HIV-1 RNA < 50 c/mL (%) 40 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 > 100,000 copies/mL, 82% treated with dolutegravir achieved HIV-1 RNA levels < 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 > 100,000 copies/mL because it takes longer for this group to reach HIV-1 RNA < 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 < 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. 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. 20 Overall ≤ 100,000 (n = 362) > 100,000 (n = 122) ABC/3TC (n = 159) TDF/FTC (n = 325) BL HIV-1 RNA (c/mL) Background NRTI Molina JM, et al. Glasgow HIV 2014. Abstract O153.

Difference in 96-Wk Cumulative Incidence (97.5% CI) ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure at Wk 96 Difference in 96-Wk Cumulative Incidence (97.5% CI) 1.00 ATV/RTV + TDF/FTC RAL + TDF/FTC DRV/RTV + TDF/FTC Favors RAL ATV/RTV vs RAL 15% (10.2% to 19.6%) 0.75 Favors RAL DRV/RTV vs RAL 7.5% (3.2% to 11.8%) Favors DRV/RTV ATV/RTV vs DRV/RTV 7.5% (2.3% to 12.7%) Cumulative Incidence 0.50 -20 -10 10 20 ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir. 0.25 24 48 64 80 96 112 128 144 Wks Since Study Entry Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

STARTMRK: Drug-Related Adverse Events 5-Yr Drug-Related AEs in ≥ 5% of Pts, % RAL + TDF/FTC (n = 281) EFV + TDF/FTC (n = 282) Gastrointestinal 21.7 29.4 Diarrhea 5.3 9.9 Flatulence 3.6 5.0 Nausea 8.9 11.0 General disorders 10.0 16.7 Fatigue 4.3 Nervous system disorders 18.5 49.6 Dizziness 7.8 35.1 Headache 9.3 14.2 Somnolence 1.1 7.4 Psychiatric disorders 30.9 Abnormal dreams 6.8 13.1 Insomnia 7.5 8.2 Nightmares 2.8 Skin and subcutaneous tissue disorders 6.0 22.3 Rash AEs, adverse events; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. Rockstroh JK, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.

HIV-1 RNA < 50 copies/mL (%) HIV-1 RNA < 50 copies/mL (%) EVG/COBI Noninferior to EFV and to ATV/RTV, With TDF/FTC, Through Wk 144 Study 102[1] Study 103[2] EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) Δ: 3.6% (-1.6 to 8.8) Δ: 2.7% (-2.1 to 7.5) Δ: 1.1% (-4.5 to 6.7) Δ: 2.7% (-2.9 to 8.3) Δ: 4.9% (-1.3 to 11.1) Δ: 3.1% (-3.2 to 9.4) HIV-1 RNA < 50 copies/mL (%) 100 88 HIV-1 RNA < 50 copies/mL (%) 100 90 84 87 84 82 83 80 82 78 80 75 80 75 60 60 ATV, atazanavir; BL, baseline; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. 40 40 20 20 Wk 48 Wk 96 Wk 144 Wk 48 Wk 96 Wk 144 1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 2. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

Treatment Difference (95% CI) Studies 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint) Virologic Outcome Treatment Difference (95% CI) 100 92 Favors E/C/F/TDF Favors E/C/F/TAF 90 E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) 80 60 4.7% ‒0.7% 2.0% HIV-1 RNA <50 c/mL (%) 40 20 4 4 4 6 C, cobicistat; D/C, discontinued; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil. Success Failure No Data ‒12% +12% CD4+ significantly higher for TAF than TDF (P = .024) D/C for adverse events: TAF 0.9%, TDF 1.5% Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%) Wohl D, et al. CROI 2015. Abstract 113LB.

Integrase Inhibitor Options for First-line Antiretroviral Therapy Drug Dosing STR Boosting Required Any Resistance in Pts With Failure Cross- Resistance Raltegravir Twice daily No Yes Elvitegravir Once daily Dolutegravir None so far Partial STR, single-tablet regimen.

DHHS Recommended Therapy Regardless of BL VL or CD4+ Count DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART Class DHHS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC† DTG + TDF/FTC Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC† DRV/COBI + TDF/FTC* NNRTI EFV/TDF/FTC RPV/TDF/FTC‡ 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load. *Only for pts with pre-ART CrCl ≥ 70 mL/min. †Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3. An alternative regimen may be the preferred regimen for some pts DHHS Guidelines. April 2015.

Virologic Nonresponse SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in Tx-Naive Pts To Wk 144 Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV) DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) 95% CI for Difference 100 80 60 40 20 Favors EFV/TDF/FTC Favors DTG + ABC/3TC 88 81 80 72 71 63 Wk 48 7.4% Pts (%) 2.5% 12.3% Wk 96 8.0% 30 2.3% 13.8% 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; HBV, hepatitis B virus; TDF, tenofovir; QD, once daily. Randomized, blinded phase III study of DTG + ABC/3TC vs EFV/TDF/FTC Outcomes at Wk 144: HIV-1 RNA < 50 c/mL: 71% (DTG) vs 63% (EFV) Virologic failure: 9% (DTG) vs 8% (EFV) No virologic data available: 18% (DTG) vs 30% (EFV) Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV) CD4 cell count increase: +379 (DTG) vs +332 (EFV) cells/mm3 (P = .003) 20 18 Wk 144 8.3% 13 10 12 5 6 7 8 7 7 2.0% 14.6% Wk 48 96 144 Wk 48 96 144 Wk 48 96 144 15% 15% Virologic Success* Virologic Nonresponse No Virologic Data *HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm. -10% noninferiority margin. Pts with HBV infection were excluded from this study. Pappa K, et al. ICAAC 2014. Abstract H-647a.

Virologic Nonresponse Nonresponse Due to Other Reasons FLAMINGO: DTG + 2 NRTIs Superior to DRV/RTV + 2 NRTIs in Tx-Naive Pts at Wk 96 Randomized, open-label phase III study of DTG + 2 NRTIs vs DRV/RTV + 2 NRTIs Protocol defined VF: <1% (2/242) with DTG vs 2% (4/242) with DRV/RTV No treatment-emergent resistance in either arm DTG + 2 NRTIs (n = 242) DRV/RTV + 2 NRTIs (n = 242) 100 80 80 68 60 Adjusted difference at Wk 96: 12.4% (95% CI: 4.7-20.2; P = .002) Pts (%) 40 21 20 12 12 8 DRV, darunavir; DTG, dolutegravir; RTV, ritonavir; TDF, tenofovir; Tx, treatment; VF, virologic failure. Randomized, open-label phase III study of DTG + 2 NRTIs vs DRV/RTV + 2 NRTIs Treatment-related d/c: 2% (DTG) vs 4% (DRV/RTV) VF: < 1% (n = 2) in each arm No treatment-emergent resistance in either arm Similar CD4+ count increase at Wk 48: +210 cells/mm³ Virologic Success* Virologic Nonresponse Nonresponse Due to Other Reasons Wk 96 *HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm. Molina JM, et al. Glasgow HIV 2014. Abstract O153.

Studies Addressing Abacavir and MI Study Association Description D:A:D[1]  Cohort collaboration (prospective) Danish HIV Cohort[2] Cohort (linked with registries) Montreal study[3] Nested case-control study SMART[4] Post hoc subgroup analysis of RCT (use of ABC not randomized) STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomized) Swiss HIV Cohort[6] Cohort (retrospective) FHDH ANRS CO4[7] ? NA-ACCORD[8] VA Clinical Case Registry[9] X Brothers et al. analysis[10] Post hoc meta-analysis of RCTs ACTG A5001/ALLRT[11] FDA meta-analysis[12] ABC, abacavir; MI, myocardial infarction; RCT, randomized controlled trial. 1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiviral Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Young J, et al. J Acquir Immune Defic Syndr. 2015. [Epub ahead of print] 7. Lang S, et al. AIDS. 2010;24:1228-1230. 8. Palella F, et al. CROI 2015. Abstract 749LB. 9. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 10. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 11. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 12. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

NA-ACCORD: Recent Abacavir Use and Risk of MI Retrospective analysis of pts in 7 clinical cohorts with recent ABC use from 1/1/1995 to 12/31/2010 “Recent” ABC initiation: prescribed within previous 6 mos ABC initiators (n = 1948) vs non-ABC initiators (n = 14,785): “Full” study population: all ART users excluding persons on ABC at study entry “Restricted” population: ART-naive persons who initiated ART in the cohort Endpoint of incident MIs: presence of clinical diagnosis or elevation of cardiac enzymes All MIs independently adjudicated Adjusted HRs for MI in Those With Recent ABC Use D:A:D Replication 1.33 Full Study 1.95 Restricted Study 1.00 2.00 3.00 4.00 Recent ABC use significant in restricted population and D:A:D replication Association diminished after adjusting for additional CVD risk factors in multivariate analysis Significant factors Both: age 60+ yrs, HTN, eGFR < 30, AIDS Full: smoking, DM ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MI, myocardial infarction. For more information about this study, go to http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202015/Highlights/Capsules/749LB.aspx. Palella F, et al. CROI 2015. Abstract 749LB.

DHHS Recommended Therapy Regardless of BL VL or CD4+ Count DHHS Guidelines: 2015 Recommended and Other Regimens for First-line ART Class DHHS Recommended Therapy Regardless of BL VL or CD4+ Count Other Regimens INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC† DTG + TDF/FTC RAL + ABC/3TC† Boosted PI DRV/RTV + TDF/FTC ATV/RTV or COBI + ABC/3TC†‡ LPR/RTV + ABC/3TC† LPR/RTV + TDF/FTC NNRTI EFV + ABC/3TC†‡ When TDF or ABC cannot be used DRV/RTV + RAL§ LPV/RTV + 3TC 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir; VL, viral load. *Only for pts with pre-ART CrCl ≥ 70 mL/min. †Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL. §Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3. DHHS Guidelines. April 2015.

DHHS Recommended Therapy Regardless of BL VL or CD4+ Count DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART Class DHHS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC† DTG + TDF/FTC Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC† DRV/COBI + TDF/FTC* NNRTI EFV/TDF/FTC RPV/TDF/FTC‡ 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load. *Only for pts with pre-ART CrCl ≥ 70 mL/min. †Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3. An alternative regimen may be the preferred regimen for some pts DHHS Guidelines. April 2015.

Evolving Options for First-line Antiretroviral Therapy

Treatment Difference (95% CI) Studies 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint) Virologic Outcome Treatment Difference (95% CI) 100 92 Favors E/C/F/TDF Favors E/C/F/TAF 90 E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) 80 60 4.7% ‒0.7% 2.0% HIV-1 RNA <50 c/mL (%) 40 20 4 4 4 6 C, cobicistat; D/C, discontinued; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil. Success Failure No Data ‒12% +12% CD4 significantly higher for TAF than TDF (P = .024) D/C for adverse events: TAF 0.9%, TDF 1.5% Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%) Wohl D, et al. CROI 2015. Abstract 113LB.

TAF vs TDF: Renal Outcomes Significantly smaller decreases in eGFR (P < .001) Significantly less proteinuria, albuminuria, and tubular proteinuria (P < .001) No cases of tubulopathy/Fanconi syndrome in either arm Discontinuations due to renal adverse events E/C/F/TAF: 0 (0%) E/C/F/TDF: 4 (0.5%) 10 Mean Change in eGFR E/C/F/TAF (n = 866) E/C/F/TDF (n = 867) 5 Mean Change (mL/min) -5 -6.6 P < .001 -10 C, cobicistat; E, elvitegravir; eGFR, eGFR, estimated glomerular filtration rate; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil. -11.2 -15 -20 0 12 24 36 48 Treatment Wk Sax PE, et al. CROI 2015. Abstract 143LB.

TAF vs TDF: Changes in Spine and Hip BMD 2 P < .001 2 P < .001 ‒0.66 ‒1.30 Mean (SD) % Change From Baseline -2 -2 ‒2.86 ‒2.95 -4 -4 BMD, bone mineral density; C, cobicistat; E, elvitegravir; F, emtricitabine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil. -6 -6 24 48 Wk 24 48 Wk E/C/F/TAF, n 845 E/C/F/TDF, n 850 797 816 784 773 836 848 789 815 780 767 Sax PE, et al. CROI 2015. Abstract 143LB.

TAF-Based Therapies in Development Studies all under way or completed EVG/COBI/FTC/TAF TAF/FTC RPV/TAF/FTC Darunavir/COBI/FTC/TAF TAF for HBV TAF/FTC for PrEP: studies planned COBI, cobicistat; EFV, efavirenz; FTC, emtricitabine; HBV, hepatitis B virus; PrEP, pre-exposure prophylaxis; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate.

DHHS Guidelines: 2015 Recommended Regimens for First-line ART Class DHHS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC† DTG + TDF/FTC Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC*† DRV/COBI + TDF/FTC* NNRTI EFV/TDF/FTC RPV/TDF/FTC‡ 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; DHHS, Department of Health and Human Services; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir; VL, viral load *Only for pts with pre-ART CrCl ≥ 70 mL/min. †Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3. DHHS Guidelines. April 2015.

Initial Factors that Influence Selection of Firstline ART Pt preference Single vs multi-pill regimens Tolerability issues Drug–drug interactions Comorbidities Potential adherence issues Adherence to regimen Adherence to follow-up care ART, antiretroviral therapy.

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