Eviplera: New First-Line Treatment Options for patients with HIV (own clinical experience in Izrael) Itsik Levy MD

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1 Eviplera: New First-Line Treatment Options for patients with HIV (own clinical experience in Izrael) Itsik Levy MD

2 Population: 8,000,000 Ethnic groups: 75% Jewish 20% Arabs 5% Others HCS PPC 3.5/1000 NPC 5/1000

3 MOH Central MOH LAB

6 The HIV clinic team

7 Continuum of HIV care in Sheba Medical Center, % % % 64% 50% 89% 57% diagnosed active follow-up treated LDL 0

8 What has been changed in our treatment in the last decade?

9 NNRTIs, from multiple pills to STR Itzchak Levy MD

10 History of NNRTIs 1996 nevirapine (viramune) 200 mg X 2 + BB 1997 deliverdine (rescriptor) 400 mg X 3 + BB 1998 efavirenz (stocrin, sustiva) 600 mg X 1 + BB 2008 etrvirine (intelence) 200 mg X 2 + BB 2011 rilpivirine (edurant) 50 mg X1 + BB 2006 ATRIPLA (truvada + efavirenz) 2011 Complera, Eviplera (truvada + rilpivirine) 2015 doravirine (in clinical studies)

11 Potential Advantages and Disadvantages of Single-Tablet Regimens Advantages Simplicity Convenience Reduces selective nonadherence to components of regimen Disadvantages 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

12 Available Single-Tablet Regimens Agent Type Yr of FDA Approval Efavirenz/tenofovir DF/ emtricitabine (EFV/TDF/FTC) Rilpivirine/tenofovir DF/ emtricitabine (RPV/TDF/FTC) Elvitegravir/cobicistat/ tenofovir DF/emtricitabine (EVG/COBI/TDF/FTC) Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) NNRTI + dual NRTI 2006 NNRTI + dual NRTI 2011 INSTI + booster + dual NRTI 2012 INSTI + dual NRTI 2014

13 DHHS; USA MAY 2014

14 DHHS; USA April 2015

16 Real national experience (Israel, ): from MTR to STR % of treated patients Lopinavir/R Old NNRTIs Darunavir/R Atazanavir/R Raltegravir Stribild Dolutegravir/Triumeq Rilpivirine/Eviplera MTR STR Year

17 Local cohort 58 patients: 50 (86%) males 5 (8%) 7 (12%) 16 (28%) 30 (52%) Naïve toxocity simplification salvage

18 Naïve patients 27 (90%) males, 25 (83.3%) MSM, 4 (13.3%) hetero, 1 (3.3%) IVDU VL at baseline 11,000 ( ) CD4 at baseline 651 ( ) Follow up period 12 M (1-20) 1-6: : 5 >12: 15 VL at last follow up 0 4 stopped: 2 due to SE (tiredness) 1 due to CD4 decrease 1 due to mutation E138A

19 LAB Creatinine mg/dl Before: /- 0.09; After: / TG mg/dl Before: 107 +/- 41; After: 100 +/- 31 TC mg/dl Before: 158 +/- 34; After: 146 +/- 19 LDL mg/dl Before: 105 +/- 26; After: 102 +/- 19 HDL mg/dl Before: 40 +/- 8; After: 37 +/- 6

20 Naïve case 31years old woman, was born in Russia, immigrated to Israel in 2003 Divorced with no children HIV+ since 2003 Her X husband was diagnosed with HIV in 2003 after a diagnosis of tuberculosis On 2003 HIV viral load was ~1000 copies/ml and CD4 count ~ 800 cells/mm 3 She returned to Russia and came back a few month ago In the last few years she suffered depression and tried to suicide On 2012: vl = 20,000 copies/ml, CD4 count=300/mm 3 DRMs: none egfr=60 ml/min/1.73m, triglycerides >350 mg/dl, hypercholesterolemia (TC > 300mg/dL, LDL 180 mg/dl) HLA B5701 positive CCR5 non trophic The patient prefers a convenient once daily prescription

21 What are the options for this patient? Atripla Eviplera Stribild Triumeq

22 Switch due to toxicities of other drugs (N=16) 13(81%) males, 11(69%) MSM, 5 (31%) hetero 6 switched from atripla due to neuropsychiatric SE 5 switched from Pis due to hyperlipidemia 2 switched from atazanavir due to Jaundice 3 for rash, neuropathy and fatigue VL at baseline 0 CD4 at baseline 716 ( ) Follow up period 12 M (1-20) 1-6: : 3 >12: 8 VL at last follow up 0 1 stopped due to CD4 decrease

23 Switch due to simplification(n=5) 3(60%) males, 2(40%) MSM, 3 (60%) hetero 3 switched from kaletra 1 switched from atazanavir 1 switched from etravirine VL at baseline 2 > 40,000; 3-0 CD4 at baseline 533 ( ) Follow up period 12 M (1-20) 1-6: : 1 >12: 1 VL at last follow up 0 none stopped

24 The classical switch case 40 years old, MSM but married + 2 children Smoker. Family history of IHD Diagnosed with HIV in 2011 due to psoriasis At diagnosis: HIV viral load: copies/ml CD4 cell count: 350 cells/mm 3 egfr: >60 ml/min/1.73m Lipid profile: normal Truvada + Efavirenz were initiated

25 The patient complained on sleep difficulties and vivid dreams but was reassured that it will become better in several weeks After 3 month viral load became undetectable, CD4 increased but the patient was depressed and nervous

26 Mollan KR, et-al: Ann Intern Med 2014

27 1 st switch Efavirenz was switched to Kaletra Within 3 weeks depression and nervousness decreased and patient was satisfied VL LDL CD4 cell count = 750 cells/mm3 But lipids now: Triglycerides 800 (before 85) mg/dl Cholesterol 240 (108) mg/dl LDL 160 (61) mg/dl HDL 40 (43) mg/dl VLDL 56 (17) mg/dl

28 2 nd switch Due to hyperlipidemia and cardiovascular RF kaletra was switched to Etravirine Vl - LDL CD4 cell count = 750 cells/mm 3 Hyperlipidemia almost normalized but PATIENT IS NOT SATISFIED!!! And wanted to stop therapy

29 3 rd switch Eviplera came to the market and Truvada + etravirine were switched to Eviplera Now VL LDL CD4 cell count = 750 cells/mm 3 Lipids normal And Patient is satisfied

30 Thank You

Third Agent Advantages Disadvantages. Component Tenofovir/emtricitabine (TDF/FTC) 300/200 mg (coformulated with EFV as Atripla) 1 tab once daily

Table I. Recommended and Alternative Antiretroviral Regimens (DHHS Guidelines, May 1, 2014) Recommended Regimens Nucleoside Analog Reverse Transcriptase Inhibitor (NRTI) Third Agent Advantages Disadvantages