Antiretroviral Therapy: What to Start

FLOWED: 05-14-2015 Chicago, IL: May 18, 2015 Antiretroviral Therapy: What to Start Eric S. Daar, MD Professor of Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles, California Slide 3 of 41 Learning Objectives After attending this presentation, participants will be able to: Explain data supporting current guidelines for what antiretroviral therapy to start Describe recommendations from current United States Guidelines for starting antiretroviral therapy Identify key factors that might influence the choice of first-line therapy INSTI NNRTI PI IAS-USA Guidelines: Recommended Regimens Elvitegravir/cobicistat/emtricitabine/tenofovir DF Dolutegravir + emtricitabine/tenofovir DF Dolutegravir + abacavir/lamivudine Raltegravir + emtricitabine/tenofovir DF Rilpivirine 1 /emtricitabine/tenofovir DF Efavirenz/emtricitabine/tenofovir DF Efavirenz + abacavir/lamivudine Günthard HF, et al. JAMA. 2014;312:410-425. Slide 5 of 41 Atazanavir + ritonavir + emtricitabine/tenofovir DF Atazanavir + ritonavir + abacavir/lamivudine Darunavir + ritonavir (qd) + emtricitabine/tenofovir DF 1 Pts with VL<100,000 and CD4>200 cells/ul Chicago, IL: May 18, 2015 1

INSTI Günthard HF, et al. JAMA. 2014;312:410-425. IAS-USA Guidelines: Alternative Regimens Raltegravir + abacavir/lamivudine NNRTI Nevirapine + 2 NRTIs Rilpivirine + abacavir/lamivudine PI Atazanavir/cobicistat + 2 NRTIs Darunavir/cobicistat + 2 NRTIs Darunavir + ritonavir + abacavir/lamivudine Lopinavir/r + 2 NRTIs Darunavir + ritonavir + raltegravir Lopinavir/r + lamivudine Lopinavir/r + raltegravir Slide 6 of 41 Regardless of Baseline HIV RNA Level or CD4 Count PI Darunavir + ritonavir (qd) + emtricitabine/tenofovir DF INSTI DHHS Guidelines April 2015: Recommended Raltegravir + emtricitabine/tenofovir DF Elvitegravir/cobicistat/emtricitabine/tenofovir DF* Dolutegravir/abacavir/lamivudine* Dolutegravir + emtricitabine/tenofovir DF Slide 7 of 41 *Available as a once-daily, single-tablet regimen Previously recommended regimens reclassified as alternative regimens Atazanavir/r + emtricitabine/tenofovir DF Greater discontinuation rates due to toxicities versus darunavir/r or raltegravir Efavirenz/emtricitabine/tenofovir DF Concerns about tolerability, especially CNS-related toxicities and possible suicidality DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision April 8, 2015. DHHS Guidelines: Alternative Regimens NNRTI PI DHHS Guidelines April 2015: Alternatives Efavirenz/emtricitabine/tenofovir DF* Rilpivirine/emtricitabine/tenofovir DF* May Be the Preferred Regimen for Some Patients *Available as a once-daily, single-tablet regimen. DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision April 8, 2015. Slide 8 of 41 Atazanavir/cobicistat + emtricitabine/tenofovir DF Atazanavir + ritonavir + emtricitabine/tenofovir DF Darunavir/cobicistat + emtricitabine/tenofovir DF Darunavir/cobicistat + abacavir/lamivudine Darunavir + ritonavir + abacavir/lamivudine Chicago, IL: May 18, 2015 2

Probability of No Virologic Failure (%) Nucleoside/Tide Reverse Transcriptase Inhibitors Slide 9 of 41 A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/ml 100 80 60 40 20 0 0 12 24 36 48 60 72 84 96 108 Weeks since Randomization No. at Risk ABC-3TC 398 363 313 267 222 188 137 87 49 20 TDF-FTC 399 361 321 284 236 204 160 104 65 23 Sax PE, et al. NEJM 2009;361:2230-2240. Probability of No Virologic Failure TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank test Hazard ratio, 2.33 (95% CI, 1.46-3.72) Slide 11 of 41 Sax PE, et al. JID 2011: 204:1191-1201 ABC/3TC vs. TDF/FTC Low Viral Load Stratum Slide 12 of 41 Chicago, IL: May 18, 2015 3

Hazard ratio Relative Risk of MI (95% CI) D:A:D Study: NRTIs and Risk of MI 1.9 1.5 1.2 1 0.8 0.6 Recent Exposure*: yes/no Cumulative Exposure: per year ZDV ddi ddc d4t 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 #MI: 523 331 148 405 554 221 139 Adjusting for egfr does not change ABC MI finding: Adjusted RR 1.89; 95% CI (1.46 2.44; P=0.0001) * Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddc) Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet 2008;371:1417-26. ** Slide 13 of 41 Bedimo R, et al. CID 2011; 53(1):84-91. VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MI 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 Unadjusted HR of AMI for each PY of exposure to each one of the categories Adjusted for estimated GFR prior to regimen onset (by MDRD method) 0.2 ABC TDF Both ABC and TDF NRTI in last regimen during obs. period Slide 14 of 41 ABC and CV Disease: NA-ACCORD Slide 15 of 41 7 Clinical cohorts from NA-ACCORD (~20%) All ART users except those on ABC at study entry Only ART naïve persons observed to have initiated ART Awaiting more comprehensive analysis using marginal structural model with time updated data (if capable of doing with relatively small sample size) Chicago, IL: May 18, 2015 4

Concerns regarding NRTIs Slide 16 of 41 Many studies have not seen relationship between ABC and CV events TDF associated with greater decline in bone mineral density TDF associated with variable decline in renal function Slide 17 of 41 Third Drug to Combine With NRTIs Reverse Transcriptase Integrase Protease CCR5 Chemokine Receptor Treatment naive; HIV-1 RNA > 2500 c/ml; susceptible to EFV, FTC, RPV, TDF (N = 786) STaR: RPV/TDF/FTC vs EFV/TDF/FTC in Treatment-Naive Patients Cohen C, et al. AIDS 2014. Abstract WEPE064. Wk 48 RPV/TDF/FTC (n = 394) EFV/TDF/FTC QD (n = 392) Wk 96 95% CI for Difference Favors Favors EFV/TDF/FTC RPV/TDF/FTC All Patients Wk 48-1.1% 4.1% 9.2% Slide 18 of 41 Wk 96-0.6% 5.5% 11.5% 78 vs. 72% BL VL 100,000 c/ml Wk 48 1.1% 7.2% 13.4% Wk 96 0.2% 7.6% 15.1% BL VL > 100,000 c/ml Wk 48-11.1% -1.8% 7.5% -8.7% 1.5% 11.6% Wk 96-12% 0 12% 86 vs. 82% Chicago, IL: May 18, 2015 5

Cumulative Incidence Mollan KR, et al. Ann Intern Med. 2014;161:1-10. Efavirenz and Suicidality Analysis of 4 ACTG studies in ART-naive patients randomly assigned to initial therapy with EFV vs EFV-free regimens HR for suicidality increased with EFV vs EFV-free regimens: 2.28 (95% CI: 1.27-4.10; P =.006) Pts at Risk, n EFV EFV free Slide 19 of 41 Cumulative Incidence of Suicidality (ITT) 0.10 EFV 0.08 EFV free 0.06 0.04 0.02 0 3241 2091 Gray P =.004 0 48 96 144 192 Wks to Suicidality 2949 1917 2703 1760 1782 1107 522 298 Treatment Naïve HIV-1 RNA 5,000 c/ml Any CD4 cell count egfr 70 ml/min GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV + TDF/FTC Randomized, Phase III, Double-blind, Double Dummy, Active-controlled, International Studies GS 102 ~89% men 33% >10 5 c/ml CD4= ~385 c/ul GS 103 ~90% men ~41% >10 5 c/ml CD4= ~370 c/ul Quad QD EFV/FTC/TDF Placebo QD EFV/FTC/TDF QD Quad Placebo QD Quad QD ATV/r +TDF/FTC Placebo QD QUAD Placebo QD ATV/r +TDF/FTC QD Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38 48 weeks 192 weeks Slide 20 of 41 95% CI for Difference Favors EFV GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV + TDF/FTC Favors EVG/COBI 3.6% Wk 48 [1] -1.6% 8.8% 84 vs. 88% 2.7% Wk 96 [2] -2.9% 8.3% 4.9% Wk 144 [3] -1.3% 11.1% 82 vs. 84% 75 vs. 80% -12% 12% 0 95% CI for Difference Favors ATV/RTV Favors EVG/COBI 2.7% Wk 48 4] -2.1% 7.5% 1.1% Wk 96 [5] -4.5% 6.7% 3.1% Wk 144 [6] -3.2% 9.4% -12% 0 12% 1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a.; 4. De Jesus E, et al. Lancet. 2012;379:2429-2438. 5. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 6. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. Slide 21 of 41 87 vs. 90% 82 vs. 83% 75 vs. 78% Chicago, IL: May 18, 2015 6

Slide 22 of 41 Study 236-102: Common Adverse Events Quad (n=348) EFV/FTC/TDF (n=352) Treatment Emergent Adverse Events in 10% of subjects (%) Diarrhea 23% 19% Nausea * 21% 14% Abnormal Dreams ^ 15% 27% Upper Respiratory Infection 14% 11% Headache 14% 9% Fatigue 12% 13% Insomnia * 9% 14% Depression 9% 11% Dizziness ^ 7% 24% Rash # 6% 12% * p<0.05; ^ p<0.001; # p=0.009 Sax P, et al, Lancet 2012: 379:2439-48 DeJesus E, et al, Lancet 2012; 379: 2429-38 Study 236-103: Adverse Events Adverse Events > 10% in Either Group Quad (n=353) ATV/r + FTC/TDF (n=355) Diarrhea 22% 27% Nausea 20% 19% Upper respiratory infection 15% 16% Headache 15% 12% Fatigue 14% 13% Ocular icterus 1% 14% Discontinuation rates due to renal events were identical in both arms (0.3%) Slide 23 of 41 EVG/COBI/TDF/FTC vs. EFV or ATV/r: Creatinine Changes Sax P, et al, Lancet 2012: 379:2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38 Slide 24 of 41 Chicago, IL: May 18, 2015 7

Dolutegravir Treatment Naïve Trials Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 SPRING-2 [1] (active controlled) SINGLE [2] (placebo controlled) FLAMINGO [3] (open label) ART-naive pts VL 1000 c/ml (N = 822) ART-naive pts VL 1000 c/ml HLA-B*5701-neg CrCL > 50 ml/min (N = 833) ART-naive pts VL 1000 c/ml (N = 484) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. ICAAC 2012. Abstract H-556b. 3. Feinberg J, et al. ICAAC 2013. Abstract H1464a. Slide 25 of 41 DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) SINGLE Study: ABC/3TC + DTG vs. TDF/FTC/EFV (96 weeks) Walmsley S, et al. NEJM 2013; 369:1807-18 16% female 14% CD4<200 cells/ul 30% VL >100,000 c/ml Slide 26 of 41 Slide 27 of 41 SPRING-2: DTG vs RAL + 2 NRTIs in Naive Patients (n = 411) (n = 411) Week 48 DTG 88%; RAL 85% Δ2. 5% (-2.2% to 7.1%) Raffi F, et al. Lancet. 2013;381:735-743; Raffi F, et al. IAS 2013. Abstract TULBPE17. Week 96 DTG 81%; RAL 76% Δ4.4% (-1.1% to 10.0%) Chicago, IL: May 18, 2015 8

Patients (%) FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Treatment Naive Clotet B, et al. Lancet 2014; 383: 2222-31 Slide 28 of 41 A5257: TDF/FTC + ATV/r, DRV/r or RAL: Virologic and Tolerability Failure N=60 5 N=60 3 N=60 1 Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) ATV/r vs RAL 3.4% (-0.7%, 7.4%) -20-10 0 10 20 76% female, 34% White HIV RNA 4.6 log 10 c/ml (30% >10 5 c/ml) CD4 308 cells/ul (30% <200 cells/ul) DRV/r vs RAL 5.6% (1.3%, 9.9%) ATV/r vs DRV/r -2.2% (-6.7%, 2.3%) Lennox J, et al. Ann Intern Med 2014; 161:461-71 Tolerability Failure Slide 29 of 41 Difference in 96 wk cumulative incidence (97.5% CI) Favors ATV/r vs RAL RAL 13% (9.4%, 16%) Favors DRV/r -20-10 0 10 20 DRV/r vs RAL 3.6% (1.4%, 5.8%) ATV/r vs DRV/r 9.2% (5.5%, 13%) Study 114: Atazanavir and FTC/TDF with Cobicistat vs. Ritonavir HIV RNA <50 Copies/mL ATV + COBI + FTC/TDF (n=344) ATV + RTV + FTC/TDF (n=348) Difference (%): -2.2 (-7.4, 3.0) 85% 87% Gallant JE, et al. J Infect Dis. 2013;208:32-39. Gallant JE, et al. 54 th ICAAC. Washington, DC, 2014. Abstract H-647. Difference (%): -2.1 (-8.7, 4.5) 72% 74% Week 48 Week 144 Slide 30 of 41 Chicago, IL: May 18, 2015 9

Slide 31 of 41 Study 130: Darunavir/Cobicistat + 2 NRTIs in Treatment-Naïve and Experienced Patients Darunavir/cobicistat + 2 NRTIs was well tolerated No new safety findings Virologic response rate 83% Similar response rates irrespective of baseline HIV RNA Similar to results form the ARTEMIS trial Pharmacokinetic data support the once-daily administration of darunavir/cobicistat 800/150 mg Tashima K, et al. J Int AIDS Soc. 2014;17(suppl 3):19772. Abstract P240. Preliminary Week-48 Outcomes (Treatment-Naïve Cohort) Patients (n=295) HIV RNA <50 copies/ml (%) 83 CD4 gain (cells/mm 3 ) 169 Treatment-emergent grade 3/4 (%) Adverse events Increased creatine kinase ALT/AST 7 8 3/2 Discontinuations due to adverse events (%) 5 Most common adverse events (%) Diarrhea Nausea Upper respiratory tract infection Headache 27 23 15 12 Cobicistat Summary FDA approval (September 2014) Increase systemic exposure of atazanavir or darunavir (once-daily) Atazanavir + cobicistat (Study 114 [phase 3]) 300 + 150 mg qd in treatment-naïve and experienced patients Slide 32 of 41 Darunavir + cobicistat (multiple-dose study in healthy volunteers showing bioequivalence to darunavir/r 800/100 mg) 800/150 mg qd in treatment-naïve and experienced patients Additional considerations Not interchangeable with ritonavir for darunavir 600 mg, fosamprenavir, saquinavir, or tipranavir due to lack of data Caution in extrapolating drug-drug interactions with ritonavir to cobicistat Cobicistat effect on renal tubular handling of creatinine (not recommended with tenofovir DF if CrCl <70 ml/min Patient or Regimen Pre-ART characteristics CD4<200 c/ul HIV RNA >100,000 c/ml HLA-B*5701 positive Treat prior to resistance ART-specific characteristics One pill once daily Food effect Individualizing First-line Therapy: Specific Circumstances Agents Slide 34 of 41 No RPV or DRV/r plus RAL No RPV, ABC/3TC with EFV or ATV/r or DRV/r + RAL No ABC Avoid NNRTIs (some would avoid INSTIs) DTG/ABC/3TC; EFV/TDF/FTC; EVG/c/TDF/FTC; RPV/TDF/FTC (if HIV RNA <100K and CD4>200 c/ul) Regimens with food: ATV, DRV, EVG/c/TDF/FTC, RPV/TDF/FTC; EFV without food DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision April 8, 2015. Chicago, IL: May 18, 2015 10

Slide 35 of 41 Individualizing First-line Therapy: Specific Circumstances Patient or Regimen Presence of other conditions CKD (CrCl <60 ml/min) Osteoporosis Psychiatric illness HIV-associated dementia Narcotic replacement therapy Cardiovascular risk factors Hyperlipidemia Risk for pregnancy Pregnancy Agents Consider avoiding TDF (if <70 ml/min avoid EVG/c, ATV/c, DRV/c with TDF) Consider avoiding TDF Consider avoiding EFV Avoid EFV if possible; favor DRV or DTG for CNS penetration Either avoid EFV or increase methadone dose if EFV is used Consider avoiding ABC and LPV/r PI/r, ABC, EFV and EVG/c associated with increase; TDF with decrease Avoid EFV Per pregnancy guidelines DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision April 8, 2015. Patient or Regimen Presence of coinfections HBV infection HCV treatment required TB infection Concerns regarding adherence Individualizing First-line Therapy: Specific Circumstances Agents Use TDF/FTC (or 3TC) when possible (if TDF contraindicated use entecavir) Refer to HIV/HCV co-infection guidelines Slide 36 of 41 If RIF used can use EFV or double dose RAL or DTG; if PI-based regimen use dose-adjusted rifabutin Pharmacologically boosted protease inhibitors Possibly DTG-based regimen DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision April 8, 2015. Slide 37 of 41 GS 104/111: FTC/COBI/EVG with TDF vs. TAF Wohl D, et al. 22 nd CROI 2015, Seattle WA, Abst. 113LB Chicago, IL: May 18, 2015 11

Wohl D, et al. 22 nd CROI 2015, Seattle WA, Abst. 113LB GS 104/111: Efficacy Slide 38 of 41 GS 104/111: Renal and Bone Sax P, et al. 22 nd CROI 2015, Seattle WA, Abst. 143LB Slide 39 of 41 Thank You Slide 41 of 41 Chicago, IL: May 18, 2015 12

SUGGESTED READINGS Gunthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA panel. JAMA. 2014;312(4):410-425. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 13, 2015. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Accessed on May 13, 2015. Gallant JE, Koenig E, ndrade-villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis. 2013; Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV- 1 infection. N Engl J Med. 2013;369(19):1807-1818. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161(7):461-471. Chicago, IL: May 18, 2015 13