More Options, Some Opinions Initial Therapies for HIV Judith S. Currier, MD More Options, Some Opinions: Initial Therapies for HIV Judith S. Currier, MD University of California Los Angeles Los Angeles, California FLOWED: 4-22-215 Slide 3 of 38 Learning Objectives After attending this presentation, participants will be able to: Describe recent changes in the DHHS guidelines for initiating first line antiretroviral therapy Distinguish between the currently available treatment options Develop an approach to selecting first line ART. What to start 5 year old woman with HIV, CD4 58 and HIV RNA 52, copies/ml PMH notable for Osteopenia (takes daily calcium supplement QID) Hypertension on treatment Obesity FH of CAD (father MI at age 52) Slide 4 of 38 Baseline labs: WNL, normal creatinine and lipids, no proteinuria Genotype: wild type virus $$$City, State: Date$$$ Page 1
DHHS Guidelines, May 214: What to Start Recommended Regimens NNRTI based Boosted PI based INSTI based EFV/TDF/FTC ATV/r + TDF/FTC DRV/r + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + TDF/FTC DTG/ABC/3TC Other recommended Regimens if baseline VL <1, c/ml NNRTI based PI based EFV + ABC/3TC RPV/TDF/FTC ATV/r + ABC/3TC DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, May 214 Slide 7 of 38 DHHS Guidelines, April 215: What to Start Recommended Regimens Boosted PI based INSTI based DRV/r + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC (CrCL > 7 ml/min) DTG + TDF/FTC DTG/ABC/3TC (HLA B-57*1 neg) Alternative Regimens (may be preferred for some patients) NNRTI based EFV/TDF/TC RPV/TDF/FTC (VL < 1, and CD4 > 2) PI based ATV/r + TDF/FTC ( Cr Cl > 7) DRV/r + ABC/3TC (HLA B57*1 neg only) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, May 214 Slide 8 of 38 IAS-USA Guidelines, July 214 What to Start Class NNRTI Boosted PI INSTI Günthard HF, et al. JAMA. 214;312:41-425. Recommended Regimens EFV/TDF/FTC EFV + ABC/3TC RPV/TDF/FTC ATV/r + TDF/FTC ATV/r + ABC/3TC DRV/r + TDF/FTC DTG/ABC/3TC DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC Slide 1 of 38 Los Angeles, CA: April 29, 215 Page 2 of 11
Slide 11 of 38 Why the change for efavirenz? Analysis of participant level data from 4 completed ACTG randomized trials in treatment naïve adults included 3241 efavirenz containing regimens and 291 efavirenz free regimens Suicidality incidence per 1 person-years 8.8 (47 events) in the efavirenz group 3.66 (15 events) in the efavirenz-free group (HR, 2.28 [95% CI, 1.27 to 4.1]; P =.6). Incidence of attempted or completed suicide 2.9 (17 events) vs. 1.22 (5 events) in the efavirenz and efavirenz-free groups, (HR, 2.58 [CI,.94 to 7.6]; P =.65). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported Mollan KR et al. Ann Int Med 214;161(1)1-1. INTEGRASE INHIBITORS ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure Lennox JL, et al. Ann Intern Med 214;161:461-71. Difference in wk cumulative incidence (97.5% CI) -2-1 1 2 Favors RAL Favors RAL Favors DRV/r ATV/r vs RAL 15% (1%, 2%) DRV/r vs RAL 7.5% (3.2%, 12%) ATV/r vs DRV/r 7.5% (2.3%, 13%) Slide 12 of 38 ACTG 5257: Tolerability Failure Toxicity-Associated Discontinuation of randomized ART* ATV/r (N=65) RAL (N=63) Slide 13 of 38 DRV/r (N=61) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity 25 2 14 Jaundice/Hyperbilirubinemia 47 Other hepatic toxicity 4 1 5 Skin toxicity 7 2 5 Metabolic toxicity 6 2 Renal toxicity (all nephrolithiasis) 4 Abnormal chem/heme (excl. LFTs) 2 Other toxicity 2 3 4 *Participants allowed to switch therapy for intolerable toxicity Lennox JL, et al. Ann Intern Med 214;161:461-71. Los Angeles, CA: April 29, 215 Page 3 of 11
Patients (%) Slide 14 of 38 week Bone loss is less with Raltegravir compared to Atazanavir/r or Darunavir/r with TDF +FTC: ACTG 526s Percentage change in total BMD HIP Brown T, Abs CROI 214, In Press JAIDS 215 Percentage change in lumbar spine BMD Mean percent change in visceral adipose tissue (VAT) McComsey, G. et al CROI 215 Slide 15 of 38 ATV/r 31% RAL 33% DRV/r 29% GS 12: EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through 1 8 6 4 2 88 84 82 8 75 * 1. Sax PE, et al. Lancet. 212;379:2439-24. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 213;63:-1. 3. Wohl D, et al. J Acquir Immune Defic Syndr 214;65:e118-2 EVG/COBI/TDF/FTC (n = 3) 7 7 6 8 7 1 5 Virologic Success* Virologic Failure EFV/TDF/FTC (n = 352) 9 9 11 12 15 No Data [1] [2] [3] 95% CI for Difference Favors EFV -1.6% -2.9% Favors EVG/COBI 3.6% 2.7% 4.9% 8.8% -1.3% 11.1% -12% 12% Slide 16 of 38 Los Angeles, CA: April 29, 215 Page 4 of 11
Proportion (%) Proportion (%) with <5 c/ml Patients (%) GS 13: EVG/COBI/TDF/FTC Noninferior to ATV/r + TDF/FTC Through 1 8 6 4 2 9 87 83 82 78 75 EVG/COBI/TDF/FTC (n = 353) 5 5 7 7 8 7 5 8 ATV/RTV + TDF/FTC (n = 355) 1. DeJesus E, et al. Lancet. 212;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 213;62:3-6. 3. Clumeck N, et al. J Acquir Immune Defic Syndr. 214;65:e121-4 11 14 18 Virologic Success* Virologic Failure No Data 95% CI for Difference Favors ATV/RTV [1] [2] -4.5% [3] -2.1% Favors EVG/COBI 2.7% 1.1% 3.1% 7.5% 6.7% -3.2% 9.4% -12% 12% Slide 17 of 38 SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC 1 9 8 7 6 5 4 3 2 1 DTG+ABC/3TC: 88% EFV/TDF/FTC: 81% WK difference in response (95% CI): +7.4% (+2.5% to +12.3%); p=.3 DTG 5 mg + ABC/3TC QD EFV/TDF/FTC QD BL 2 4 8 12 16 24 32 4 Week DTG + ABC/3TC QD superior to EFV/TDF/FTC at (1 o endpoint) Walmsley S, et al. N Engl J Med 213;369:187-18 Slide 15 of 38 FLAMINGO: DTG superior to DRV/r VL <5 c/ml at Week, Snapshot analysis 1 8 6 4 2 9 83 Virologic success DTG 5 mg QD (N=242) DRV/r 8/1 mg QD (N=242) 6 7 1 4 Virologic non-response No Week data 95% CI for difference a Favors Favors DRV/r DTG.97.1 13.2-2% -12% 2% Test for superiority: P=.25 Feinberg et al. ICAAC 213; Denver, CO. Abstract H-1464a. Slide 19 of 38 Los Angeles, CA: April 29, 215 Page 5 of 11
Percentage of Subjects (%) Slide 2 of 38 Comparing the integrase inhibitors Agent Advantages Disadvantages Raltegravir Elvitegravir Dolutegravir Longest experience Fewest drug interactions Single-tablet regimen (STR) Once-daily dosing The only non-tdf-containing STR Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RAL-and EVG-resistant virus Twice daily dosing (for now) No coformulation Requires COBI boosting COBI drug interactions similar to RTV Co-formulated only with ABC/3TC Divalent cations reduce absorption: adjust timing The results of STARMRK, GS 12 and 13, SINGLE, FLAMINGO, and ACTG 5257 suggest that integrase inhibitor-based regimens are the preferred starting regimens in the majority of patients. PROTEASE INHIBITORS 1 85 87 78 79 8 72 74 6 4 2 GS 114: ATV/COBI vs. ATV/r with TDF/FTC Snapshot Weeks,, (ITT) COBI (n=344) RTV (n=3) 2 21 15 16 6 7 8 9 9 4 5 5 W W W W W W W W W Virologic Success Virologic Failure No data * 95% CI for Difference Favors Favors ATV + RTV ATV + COBI -7.4 3. Slide 21 of 38 * No data include: DC study drug due to AE/death; DC study drug (other reasons) and last available HIV-1RNA < 5c/mL; Missing data during window -12% W W W -8.7-2.2-2.1 Mean CD4 cell increase (cells/mm 3 ) was 31 (COBI) vs 332 (RTV) Gallant JE, et al. ICAAC 214, Washington, DC. Abstract H-647. 4.5 12% Now Approved ATV/cobi 3/1 mg once daily DRV/cobi 8/1 mg once daily Slide 22 of 38 Only for patients with no DRV resistance mutations Los Angeles, CA: April 29, 215 Page 6 of 11
% of those with given CVD risk receiving ABC NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Studies addressing association between abacavir and MI Study Association? Description D:A:D Cohort collaboration (prospective) Danish HIV Cohort Cohort (linked with registries) Montreal study Nested case-control study SMART Post-hoc subgroup analysis of RCT (use of ABC not randomised) STEAL Pre-planned secondary analysis of RCT (use of ABC randomised) Brighton study Nested case-control study VA Clinical Case Registry Cohort (retrospective) FHDH ANRS CO4? Nested case-control study Boston Cohort Cohort (retrospective) GSK studies Post-hoc meta-analysis of RCTs ACTG A51/ALLRT Post-hoc meta-analysis of RCTs FDA meta-analysis Post-hoc meta-analysis of RCTs Sabin C, et al. CROI 213 Slide 23 of 38 D:A:D 214 Use of ABC in cohort over time 35 3 25 2 15 1 5 D:A:D presentation March 28 RR. 1.97 (1.68, 2.33) RR 1.97 (1.43, 2.72) Low CVD risk Mod CVD risk High CVD risk CVD risk U/K Total cohort Slide 24 of 38 Sabin C, et al. CROI 213 NA-ACCORD: Recent Abacavir Use and Risk of MI Retrospective analysis of pts in 7 clinical cohorts with recent ABC use (prescribed in previous 6 mos) from 1/1/1995 to 12/31/21 ABC initiators (n = 19) vs noninitiators (n = 14,785): Full study population: all ART users excluding those on ABC at entry Restricted population: ART-naive pts who started ART in the cohort Endpoint of incident MIs: presence of clinical diagnosis or elevation of cardiac enzymes Palella F, et al. CROI 215. Abstract 749LB. D:A:D Replication Full Study Restricted Study 1.33 1.95. 1. 2. 3. 4. Recent ABC use significant in restricted population and D:A:D replication Significant predictors: Both: Age 6+, HTN, egfr < 3, AIDS Full: Smoking, DM Slide 25 of 38 Adjusted HRs for MI in Those With Recent ABC Use Los Angeles, CA: April 29, 215 Page 7 of 11
NRTI-Sparing Regimens Slide 26 of 38 Slide 27 of 38 NEAT 1: DRV/r + either RAL or TDF/FTC: Primary endpoint at W by baseline characteristics Overall n = 85 Baseline HIV-1 RNA < 1, c/ml n = 53 Baseline CD4+ < 2/mm 3 > 2/mm 3 n = 123 n = 682-1.1 8.6-3.9 3.5 > 1, c/ml n = 275 -.5 19.3 Raffi et al, CROI214, Abstract 84LB -3.4 6.3 4.7 3.8 9-1 1 2 3 RAL + DRV/r 17.4 % 7 % 36 % 39. % 13.6 % TDF/FTC + DRV/r 13.7 % 7 % 27 % p =.9 21.3 % 12.2 % p =.2 Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted MODERN: MVC QD + DRV/r Not Noninferior to TDF/FTC + DRV/r Pts With HIV-1 RNA < 5 copies/ml [1] 1 8 6 4 2 BL 4 8 12 16 2 24 36 86.8% Adjusted treatment difference (95% Cl): -9.5% (-14.8% to -4.2%) Stellbrink H-J, et al. AIDS 214. Abstract MOAB11. Slide 28 of 38 TDF/FTC + DRV/r (n = 41) MVC + DRV/r (n = 3) 77.3% Similar rates of VL suppression at Week by screening assay type Assay Type MVC + DRV/r (n = 3) TDF/FTC + DRV/r (n = 41) Phenotypic 74.4 87. Genotypic 8.7 86.5 Δ (95% CI) 6.9% (1.3% to 15%) Los Angeles, CA: April 29, 215 Page 8 of 11
Patients (%) GARDEL: LPV/r + 3TC noninferior to LPV/r + 2 NRTIs at Δ 4.6 (95% CI: -2.2 to 11.8; P =.171) 1 88.3 83.7 8 6 4 Dual ART (n = 214) Triple ART (n = 22) 2 4.7 5.9.9 4.9 6.1 5.4 n = 189 169 1 12 2 1 13 11 Virologic Virologic D/C Due D/C for Success* Nonresponse to AE or Other Death Reasons *VL< 5 c/ml by FDA Snapshot algorithm. Slide 29 of 38 CD4 count increase similar Grade 2-3 AEs more frequent in triple-art arm (88 vs 65 events) VF in 22 pts, of whom 2 had resistance (M184V) Both on dual ART Cahn P, et al. Lancet Infect Dis 214;14:572-8 NRTI-sparing regimens Regimen Results DRV/r + RAL (ACTG 5262 1 ) Poor performance at high VL DRV/r + RAL (NEAT 2 ) Less effective at high VL, low CD4 DRV/r + MVC (MODERN 3 ) Less effective than standard ART ATV/r + RAL (HARNESS 4 switch) Less effective than standard ART LPV/r + RAL (PROGRESS 5 ) Small study; few pts with high VL LPV/r + EFV (ACTG 5142 6 ) Poorly tolerated but effective LPV/r + 3TC (GARDEL 7 ) As effective as standard ART LPV/r + 3TC or FTC (OLE 8 switch) As effective as standard ART ATV/r + 3TC (SALT 9 switch) As effective as standard ART 1. Taiwo B, et al. AIDS. 211;25:2113-22 6. Daar ES et al. Ann Intern Med 211 2. Raffi et al. CROI 214, Abstract 84LB 7. Cahn P, et al. Lancet Infect Dis 214;14:572-8 3. Stellbrink H-J, et al. IAD 214. Abstract MOAB11 8. Gatell J, et al. AIDS 214. Abstract LBPE17. 4. Van Lunzen J et al. IAC 214. Abstract A-641-126-1137 9. Perez-Molina, J.A., et al. IAC 214. AbstractL BPE18. 5. Reynes J, et al. AIDS Res Hum Retroviruses. 213;29:256-65 Slide 3 of 38 Slide 31 of 38 How to select a nuke-sparing regimen when you need one All NRTI-sparing regimens should include a boosted PI for now LPV/r + EFV was effective but poorly tolerated, but other PI/NNRTI combinations could be considered Boosted PI + INSTI may not be enough Opinions: (DRV/r or DRV/c) + DTG + (3TC or FTC) (DRV/r or DRV/c) + ETR (+/- 3TC or FTC) (DRV/r or DRV/c) + (3TC or FTC)? Los Angeles, CA: April 29, 215 Page 9 of 11
VL < 5 c/ml by Snapshot Algorithm (%) LATTE: Virologic Success Through Maintenance Week Induction Phase 1 8 6 4 2 EFV 6 mg (n = 62) BL 4 12 24 28 36 72 6 pts in CAB arms with PDVF at ; 4 additional pts since Margolis D, et al. CROI 215. Abstract 554LB. s Maintenance Phase CAB 1 mg (n = 6) CAB 3 mg (n = 6)* CAB 6 mg (n = 61) 84% 75% 68% 63% Slide 32 of 38 *Cabotegravir 3 mg selected for future development What about generic ART? Generic drugs currently available: zidovudine, lamivudine, nevirapine, efavirenz (only as single tablets at this time) 216- abacavir, lopinavir/r patent s expire 217/18 tenofovir, darunavir/r and atazanavir/r expected Slide 33 of 38 Fixed dose combinations have obtained extension of patent protection, but eventually single tablet regimens will be available Modeling estimates predict enormous cost savings if generics are used 1,2 - but at what cost to patient outcomes? 1. Walensky R et al. Ann Int Med 213;158(2):84-92 2. Hill, A, et al. International Congress of Drug Therapy in HIV Infection, abstract -216, Glasgow, 214. From: Economic Savings Versus Health Losses: The Cost-Effectiveness of Generic Antiretroviral Therapy in the United States Ann Intern Med. 213;158(2):84-92. doi:1.7326/3-19-158-2-213115-2 Table Title: Tradeoffs Between Generic-Based and Branded ART Date of download: 4/3/215 Copyright American College of Physicians. All rights reserved. Slide 34 of 38 Los Angeles, CA: April 29, 215 Page 1 of 11
Summary and Conclusions ART has evolved to several safer, simpler options Slide 36 of 38 Growing evidence favoring INSTI based regimens, however PI and NNRTI options have strong track record Individualizing therapy remains key Drug interactions Continued need for data on comparative long term outcomes Generics on the horizon, but treatment continues to evolve Los Angeles, CA: April 29, 215 Page 11 of 11