11/7/2016. Antiretroviral Therapy Strategies. Learning Objectives. After attending this presentation, participants will be able to:

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1 Antiretroviral Therapy Strategies FORMATTED: 1/14/16 Joel E. Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine The Johns Hopkins University Baltimore, Maryland Financial Relationships With Commercial Entities Dr Gallant has served as a consultant or advisor to Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Merck & Co, Inc, Theratechnologies, Inc, and ViiV Healthcare/GlaxoSmithKline. He has received research grants or contracts awarded to his institution from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Inc, Merck & Co, Inc, Sangamo BioSciences, and ViiV Healthcare/ GlaxoSmithKline. (Updated 1/28/16) Slide 2 of 51 Learning Objectives After attending this presentation, participants will be able to: Describe current approaches to immediate or rapid initiation of antiretroviral therapy Discuss data supporting switching or simplifying therapy in patients whose viral loads are suppressed on ART. List the strengths and weaknesses of two-drug regimens and induction-maintenance strategies that have been studied to date in clinical trials. Slide 3 of 51 1

2 According to treatment guidelines which of the following is not a valid reason to switch therapy in a virologically suppressed patient? 2% 1. To simplify dosing 12% 22% 2% 62% 2. To eliminate food restrictions 3. To ensure the patient is on a recommended regimen 4. To prevent toxicity 5. None of the above. (All are valid reasons to switch) Slide 4 of 51 J.P. Slide 4 of 51 JP is a 28-yr-old, otherwise healthy graduate student, recently diagnosed with HIV infection Baseline labs: CD4 count 653 VL is 36, Genotype: wild-type virus Normal renal function, transaminases, lipids HBsAg, HCV negative His partner is HIV negative. They occasionally have sex with other partners. STD screening is negative He will start ART if you recommend it, and believes he will be adherent J.P. What would you start? Slide 6 of 51 % 1. EFV/FTC/TDF 5% 2. RPV/FTC/TDF 42% 3. EVG/c/TAF/FTC 26% 4. DTG/ABC/3TC 26% 5. DTG + FTC/TAF % 6. FTC/TAF + either DRV/c or DRV/r % % 7. Something else 8. I would defer therapy 2

3 DHHS Guidelines, July 216: What to Start Slide 6 of 51 Recommended regimens PI based DRV/r + (TDF/FTC or TAF/FTC) INSTI based RAL + (TDF/FTC or TAF/FTC) EVG/c/TDF/FTC or EVG/c/TAF/FTC DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC Alternative regimens NNRTI based EFV/TDF/FTC or EFV + TAF/FTC RPV/TDF/FTC or RPV/TAF/FTC (VL <1,; CD4 >2) PI based (ATV/c or ATV/r) + (TDF/FTC or TAF/FTC) (DRV/c or DRV/r) + ABC/3TC DRV/c + (TDF/FTC or TAF/FTC) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, July 216. IAS USA Guidelines, July 216 What to Start Slide 7 of 51 Recommended Regimens DTG/ABC/3TC DTG + TAF/FTC EVG/c/TAF/FTC RAL + TAF/FTC Options When INSTIs are Not an Option DRV/c or DRV/r + (TAF/FTC, TDF/FTC or ABC/3TC) EFV/FTC/TDF RPV/FTC/(TAF or TDF) Günthard HF, et al. JAMA 216;316: T.F. Slide 9 of year-old gay man is diagnosed with HIV on a routine test He tested negative 1 year earlier. He was given antibiotics for a mono-like illness 6 months ago at an urgent care center He has been having condomless sex with multiple partners. He asked his doctor about PrEP and was told he should find a specialist. He sees a nurse and case manager the day after diagnosis, and baseline labs are drawn. He will see an HIV provider in 1 days. He is interested in starting ART. 3

4 Slide 1 of 51 T.F. When would you start ART? % 1. After he keeps several clinic appointments (~3 months) 17% 12% 1% 61% 2. After baseline genotype results are available (~2-3 wks) 3. At the HIV provider visit (1 days) 4. If creatinine is normal and HBsAg is negative (1-2 days) 5. Today RAPID Intervention Components Slide 11 of 51 Facilitation of same day appointments Flexible scheduling for providers (on-call back-up) ART regimens pre-approved for use prior to genotyping or lab testing Available as 5 day starter packs Accelerated process for health insurance initiation Recommendation for 1 st dose to be taken observed in the clinic Pilcher CD, et al. J Acquir Immune Defic Syndr 216 Engagement Timeline, SFGH Slide 12 of 51 Referral 1 st Clinic Visit 1 st PCP Visit ART Prescribed Viral load suppressed CD4-guided (26-9) Universal (21-3) RAPID 1 56 Pilcher CD, et al. J Acquir Immune Defic Syndr 216 4

5 Slide 13 of 51 T.F. The nurse calls in an HIV provider, who meets with patient briefly. ART is started immediately, with plans to follow up at scheduled visit in 1 days Which of the following regimens would you start? 7% 1. EVG/c/FTC/TAF 77% 2. DTG + FTC/TAF 1% 3. DTG/ABC/3TC 7% 4. DRV/c + FTC/TAF % 5. RPV/FTC/TAF % 6. EFV/FTC/TDF Rapid Start: Potential regimens Slide 14 of 51 Regimens to consider DTG + FTC/TAF EVG/c/FTC/TAF DRV/c + FTC/TAF Drugs to avoid ABC (need HLA B*571) TDF (need egfr) RPV (need VL, CD4) EFV, NVP (need genotype) D.F. Slide 15 of year-old man with HIV since 28. His nadir CD4 count was 362 and peak VL was 89,. Has been on EFV/TDF/FTC since diagnosis, with undetectable VL and a CD4 >5 2 years ago he declined switch to a newer regimen because he had no side effects other than vivid dreams, which he usually enjoyed, and he wanted a single-tablet regimen egfr consistently >6 Other medications: losartan 5 mg/d and atorvastatin 1 mg/d HLA B*571-negative 5

6 Slide 16 of 51 D.F. What do you recommend now? 37% 1. Make no changes 11% 2. Suggest switch to EFV + FTC/TAF 21% 3. Suggest switch to DTG/ABC/3TC 5% 4. Suggest switch to EVG/c/FTC/TAF 11% 5. Suggest switch to DTG + FTC/TAF 16% 6. Order bone density scan before deciding Switching therapy in suppressed patients: When and why? To manage side effects To manage or prevent drug toxicity To simplify regimen (number of doses or pills) To address food restrictions To address drug interactions To plan for pregnancy GS 189: Switch from F/TDF to F/TAF Weeks 48 and 96 Efficacy Virologic Outcome Treatment Difference (95% CI) FTC/TAF (n=333) FTC/TDF (n=33) FTC/TDF FTC/TAF Patients, % Wk Week Wk Success (< 5 copies/ml) Failure No Virologic Data FTC/TAF noninferior to FTC/TDF at Weeks 48 and 96 Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 6

7 GS 1216: RPV/FTC/TDF to RPV/FTC/TAF Virologic Suppression at Week 48 (FDA snapshot) Virologic Outcome Treatment Difference, % (95% CI) RPV/FTC/TAF n=316 RPV/FTC/TDF n=313 Patients, % <1 Success Failure No Data n= Efficacy comparable across age, sex, geographic region No emergent resistance mutations detected in either group Orkin C, et al. HIV Glasgow 216, Glasgow, UK GS-116: EFV/FTC/TDF to RPV/FTC/TAF Virologic Suppression at Week 48 (FDA snapshot) Virologic Outcome Treatment Difference, % (95% CI) RPV/FTC/TAF n=438 EFV/FTC/TDF n=437 Patients, % Success Failure No Data n= Efficacy comparable across age, sex, geographic region No emergent resistance mutations detected in RPV/FTC/TAF group 1 pt in EFV/FTC/TDF group developed mutations (M184V, V16I/L, Y188L) Orkin C, et al. HIV Glasgow 216, Glasgow, UK 7 GS 189: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Weeks 48 and 96 FTC/TAF FTC/TDF egfr Urine Protein:Cr Urine Albumin:Cr Urine RBP:Cr Urine β2m:cr Median Change, ml/min Median % Change All differences between treatments statistically significant (p <.1) Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 7

8 GS 1216 and 116: Change in egfr at Week 48 Study 1216 Study 116 RPV/FTC/TAF RPV/FTC/TDF RPV/FTC/TAF EFV/FTC/TDF Median (Q1, Q3) Change egfr (ml/min)* p= p < Week Week Orkin C, et al. HIV Glasgow 216, Glasgow, UK GS 189: Switch from F/TDF to F/TAF: Bone density changes through Week 96 Spine Hip Mean % Change (95% CI) p < p < n Week Week FTC/TAF FTC/TDF FTC/TAF FTC/TDF p value FTC/TAF FTC/TDF p value 3% increase 4% 18% <.1 29% 11% <.1 3% decrease 8% 19% <.1 6% 15% <.1 Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 GS 1216 and 116 Change in Spine BMD Through Week 48 Study 1216 Study 116 RPV/FTC/TAF RPV/FTC/TDF RPV/FTC/TAF EFV/FTC/TDF Mean % Change (95% CI) p <.1 p < BL Wk 24 Wk 48 BL Wk 24 Wk 48 (n=) (n=) (n=) (n=) RPV/FTC/TAF RPV/FTC/TDF RPV/FTC/TAF EFV/FTC/TDF 27% 11% 29% 13% 3% increase p<.1 p<.1 3% decrease 6% 13% p=.44 7% 14% p=.1 Orkin C, et al. HIV Glasgow 216, Glasgow, UK 8

9 TDF to TAF switch Slide 25 of 39 Advantages: Greater renal safety Improved bone density Smaller pill size Disadvantages: Loss of TDF lipid effect TAF will be more expensive than generic TDF IAS-USA recommendations: If there is no increase in the price of TAF vs. that of TDF, switching from TDF to TAF is reasonable even if patients are not experiencing TDF-related toxic effects. Günthard HF, et al. JAMA 216;316: D.F. Slide 25 of 51 Outcome: D.F. decided to make a switch based on the greater safety of TAF. He considered switching to FTC/TAF + EFV but decided that the dreams weren t always enjoyable, and ended up switching to EVG/c/FTC/TAF L.M. Slide 26 of year-old massage therapist taking DRV/c + FTC/TAF with VL <2 Previously failed EFV/TDF/FTC, which he had been taking 2-3 times per week. Has K13N mutation. He does not trust western medicine, he knows his body, believes he does not tolerate standard doses of most drugs, and feels he is experiencing a build-up of toxicity without any specific side effects He is not concerned about pill burden, as he takes dozens of supplements, but he has read about monotherapy, 2-drug regimens, and intermittent therapy, and would like to reduce the number of chemicals that he takes 9

10 Slide 28 of 51 L.M. How do you approach L.M.? 1% 1. Switch to 3TC plus either DRV/c or DTG 2. Switch to DTG or DRV/c monotherapy 2% 3. Switch to DTG + RPV 25% 4. Advise him to continue his regimen at full dose pending 35% more data % 5. Advise him to take his current regimen every other day 1% 6. Suggest chelation therapy to remove toxins Nuke-sparing and nuke-lite regimens Slide 29 of 51 Regimen Results DRV/r + RAL (ACTG ) 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 ) 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 DTG + 3TC (PADDLE 1 ) Promising but preliminary 1. Taiwo B, et al. AIDS. 211;25: Daar ES et al. Ann Intern Med Raffi et al. CROI 214, Abstract 84LB 7. Cahn P, et al. Lancet Infect Dis 214;14: Stellbrink H-J, et al. IAD 214. Abstract MOAB11 8. Gatell J, et al. AIDS 214. Abstract LBPE Van Lunzen J et al. IAC 214. Abstract A Perez-Molina, JA, et al. IAC 214. Abstract LBPE Reynes J, et al. AIDS Res Hum Retroviruses. 213;29: Figueroa MI, et al. EACS 215. Abstract 166. GARDEL: LPV/r + 3TC noninferior to LPV/r + 2 NRTIs at Wk 48 Slide 3 of 51 Patients (%) 4.6 (95% CI: -2.2 to 11.8; 1 P =.171) Dual ART (n = 214) Triple ART (n = 22) CD4 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 n = Virologic Virologic D/C Due D/C for Success* Nonresponse Death Reasons to AE or Other *VL< 5 c/ml by FDA Snapshot algorithm. Cahn P, et al. Lancet Infect Dis 214;14:

11 PADDLE: All Pts Virologically Suppressed by Wk 8 of DTG + 3TC Included 4 pts with VL > 1, at BL HIV 1 RNA (copies/ml) Pt # Screen BL Day 2 Day 4 Day 7 Day 1 Wk2 Wk3 Wk4 Wk6 Wk8 Wk12 Wk , < 5 < 5 < 5 < 5 < 5 < 5 < , < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < , ,569 37, < 5 < 5 < 5 < 5 < , ,37 11, < 5 < 5 < 5 < 5 < ,362 2, < 5 < 5 < 5 < 5 < 5 < ,24 14, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,64 18, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,71 24, Not done < 5 < 5 < 5 < 5 < 5 < ,77 1,832 Not done < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 1 1, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,89 273,676 16,974 68, < 5 < 5 < ,58 64, < 5 < 5 < 5 < ,93 33,829 37,35 26, < 5 < 5 < 5 < 5 < 5 < ,348 15, < < 5 < 5 < 5 < ,185 23,5 15, < 5 < 5 < 5 Not done < 5 < 5 < , < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,1 25,828 11, < 5 < 5 < 5 < 5 < 5 < ,771 73,69 31, < 5 < 5 < 5 < 5 < 5 < ,83 16,32 35, < 5 < 5 < 5 < 5 < < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 Figueroa MI, et al. EACS 215. Abstract 166. Slide 31 of 51 DTG Monotherapy Slide 36 of virologically suppressed patients in 4 observational studies at 4 centers switched to DTG monotherapy Virologic failure with emergence of integrase resistance occurred in 5 patients (4.4%) 4 had history of prior INSTI use, one with RAL failure. None had documented INSTI resistance Oldenbuettel C, et al. Antiviral Ther 216; Rojas J, et al. J Antimicrob Chemother 216 Jul;71: Katlama C, et al. J Antimicrob Chemother 216 Sep;71: Gubavu, C, et al. J Antimicrob Chemother 216;71: L.M. Slide 37 of 51 Outcome: L.M. agrees to remain on a 3-drug regimen for now, but asked to switch to DTG/ABC/3TC. He wants to switch to a 1- or 2-drug regimen once they are supported by stronger data 11

12 J.B. Slide 34 of year-old man who has been doing well for several years on TDF/FTC + DRV/r (6/1 mg bid) + RAL + ETR, with an HIV RNA <2 and CD4 763 He started ART in the late 8 s, and remembers taking AZT, d4t + 3TC, NVP, IDV and NFV, but there were others he doesn t remember. He knows he has some resistance. He has outlived two of his doctors, and attempts to obtain medical records from the survivors have been unsuccessful His younger friends are all on single-tablet regimens. He takes 9 pills per day and wants to switch to a once-daily regimen, with as few pills as possible (preferably one) J.B. What do you recommend? Slide 35 of 51 4% 1. EVG/COBI/FTC/TAF 1% 2. RPV/FTC/TAF 3. DTG/ABC/3TC 12% 4. EFV/TDF/FTC 1% 5. I would not recommend a single-tablet regimen, but I would simplify his 28% regimen in other ways 51% 6. I would order a proviral DNA genotype 1% 7. I would congratulate him on being alive and tell him to count his blessings and suck it up Switch studies in suppressed pts Trial From To Outcome + RAL EVG/COBI/FTC/TDF GS-123 TDF/FTC GS-264 TDF/FTC/EFV RPV/FTC/TDF Strategy-NNRTI TDF/FTC + NNRTI EVG/COBI/FTC/TDF Strategy-PI TDF/FTC + PI/r EVG/COBI/FTC/TDF SPIRIT 2 NRTI + PI/r RPV/FTC/TDF SPIRAL 2 NRTI + PI/r (exp d pts) 2 NRTI + RAL SALT ATV/r + 2 NRTI ATV/r + 3TC OLE LPV/r + 2 NRTIs LPV/r + 3TC GS-19 TDF-based ART EVG/COBI/FTC/TAF STRIIVING Suppressive ART DTG/ABC/3TC ATLAS-M ATV/r + 2 NRTIs ATV/r + 3TC GS-119 Salvage regimen EVG/COBI/FTC/TAF + DRV LATTE CAB or EFV + 2 NRTIs CAB + RPV (PO) GS-189 TDF/FTC + 3 rd agent TAF/FTC + 3 rd agent LATTE-2 CAB + ABC/3TC CAB + RPV (IM) GS-116 EFV/FTC/TAF RPV/FTC/TAF GS-1216 RPV/FTC/TDF RPV/FTC/TAF SWITHCMRK 2 NRTI + LPV/r (exp d pts) 2 NRTI + RAL HARNESS 2 NRTI + 3 rd Agent ATV/r + RAL Slide 36 of 51 12

13 SWITCHMRK: Prior failure predicts failure Slide 37 of 51 Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure SWITCHMRK1 SWITCHMRK 2 Outcome RAL LPV/r (n = RAL LPV/r (n = (n = 174) 174) (n = 176) 178) Patients without previous virologic failure VL < 5 at Wk 24, % Treatment difference, % (95% CI) ) ) (-9.9 to (-8.5 to Patients with previous virologic failure VL < 5 at Wk 24, % Treatment difference, % (95% CI) to -2.5) to -2.6) (-33. (-26.5 Eron JJ, et al. Lancet. 21;375: Switching: Caveats Slide 38 of 51 Know the treatment and resistance history Avoid switching from high barrier to lower barrier agents when you don t Slide 39 of 51 Concordance with historical resistance (individual ARVs): 85% NNRTIs: 93% PIs: 84% NRTIs: 76% Identified major wild-type (nonmutant) variants at 97% False omission rate 3%. Toma J, et al. ICAAC 215, September 17-21, 215, San Diego. 13

14 Slide 4 of 51 J.B. GenoSure Archive results NRTI: 67N,184V, 219Q NNRTI: 13N PI: 1V, 54V, 63P, 71V, 77I, 82A, 9M INSTI: no mutations (DRV mutations: V11I, V32I, L33F, I47V, I5V, I54L, I54M, T74P, L76V, I84V, L89V) J.B. Slide 41 of 51 What do you recommend now? GS 119: E/C/F/TAF + DRV for treatmentexperienced patients Slide 48 of 51 Randomized (2:1), open-label (N=135) Eligibility: 4 mos <5 on ART containing DRV 2 prior failures 2-class resistance by historical genotype (inc. 3 TAMs and K65R) Historical genotype with no INSTI-R or currently on RAL No Q151M, T69ins, or DRV RAMS egfr >5 ml/min Week Primary Efficacy Endpoint 24 n=89 E/C/F/TAF + DRV 8 mg QD n=46 Baseline Regimen (BR) 48 E/C/F/TAF + DRV 8 mg QD 144 Objectives Primary Efficacy of E/C/F/TAF + DRV vs. BR at Week 24: FDA snapshot (<5) Secondary Safety and tolerability in both treatment arms over 24 and 48 weeks Efficacy at Week 48: VL <5 Efficacy at Week 48: VL <2 Huhn G, et al. IDWeek

15 GS 119: Baseline Characteristics Slide 49 of 51 %, unless otherwise indicated E/C/F/TAF + DRV Characteristics n=89 Baseline Regimen n=46 Median age, years Male Black (or African descent) Median CD4 count, cells/μl Median egfr CG, ml/min 99 1 DM / HTN / CVD / Hyperlipidemia 8 / 34 / 7 / / 37 / 4 / 28 Baseline Regimen Median No. pills per day pills per day 4 37 At least BID dosing TDF / ABC / other NRTIs 61 / 11 / / 11 / 13 RAL 56 5 Resistance 2-class / 3-class resistance 7 / / 2 M184V/I K65R 2 3 NNRTI-R / PI-R 89/ / 28 Huhn G, et al. IDWeek 215 GS 119: Virologic Outcome at Weeks 24 and 48* VL <5 Slide 5 of Week Week E/C/F/TAF + DRV (n=89) Baseline Regimen (n=46) Success Failure No Data Success Failure No Data Huhn G, et al. IDWeek 215 Proportional 5.3% (-3.4%, 17.4%) 18.3% (3.5%, 33.%) difference (95% CI) p=.23 p=.4 At Week 48, significantly higher virologic success rate at the more stringent cutoff (VL <2) with E/C/F/TAF + DRV compared with BR (9% vs 72%, p=.12) No participants in E/C/F/TAF + DRV developed resistance; 1 participant with viral rebound (Week 36) developed resistance in the BR arm (M184V+K65R) J.B. Slide 45 of 51 Outcome: JB was switched to a 2 pill once daily regimen of EVG/c/FTC/TAF + DRV. His VL remains suppressed and he likes his new regimen. 15

16 According to treatment guidelines which of the following is not a valid reason to switch therapy in a virologically suppressed patient? 1% 1. To simplify dosing % 54% 1% 43% 2. To eliminate food restrictions 3. To ensure the patient is on a recommended regimen 4. To prevent toxicity 5. None of the above. (All are valid reasons to switch) Slide 46 of 51 According to treatment guidelines which of the following is not a valid reason to switch therapy in a virologically suppressed patient? To simplify dosing 1% 2% To eliminate food restrictions % 12% To ensure the patient is on a recommended regimen 22% 54% To prevent toxicity 1% 2% None of the above. (All are valid reasons to switch) 43% 62% Slide 47 of 51 First Slide Second Slide Antiretroviral Therapy Strategies FORMATTED: 1/14/16 Joel E. Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine The Johns Hopkins University Baltimore, Maryland 16