HIV Treatment Update 8/3/2015. When to Start. Disclosures

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1 8/3/215 HIV Treatment Update Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, NM University of New Mexico School of Medicine Johns Hopkins University School of Medicine Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Takara Bio, Inc. Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare When to Start No news is good news! 1

2 Cumulative Percent With Event 8/3/215 START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts International, randomized trial Study closed by DSMB following interim analysis HIV+, ART-naive adults with CD4 > 5 (N = 4685) Immediate ART ART initiated immediately following randomization (n = 2326) Deferred ART Deferred until CD4 35, AIDS, or event requiring ART (n = 2359) Composite primary endpoint: Serious AIDS-related (AIDS-related death or AIDSdefining event) or non-aids related event (non-aids related death, CVD, end-stage renal disease, decompensated liver disease, non-aids defining cancer) Median follow-up: 3. yrs; med. baseline CD4: 651; med. baseline VL: 12,759 Median CD4 at initiation of ART for deferred group: 48 N Engl J Med [Epub ahead of print]. Lundgren J, et al. IAS 215. Abstract MOSY32. START: 57% Reduced Risk of Serious Events or Death With Immediate ART 1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-aids related event or death: HR =.43 (95% CI:.3 to.62); P < Deferred ART 4 2 Immediate ART Month N Engl J Med [Epub ahead of print]. Lundgren J, et al. IAS 215. Abstract MOSY32. START: Primary Endpoint Components With Immediate vs Deferred ART Endpoint Immediate ART Deferred ART (n = 2326) (n = 2359) N Rate/1 PY N Rate/1 PY Serious AIDS-related event Serious non-aids related event All-cause death Tuberculosis Kaposi s sarcoma Malignant lymphoma Non-AIDS defining cancer CVD N Engl J Med [Epub ahead of print]. Lundgren J, et al. IAS 215. Abstract MOSY32. HR (95% CI)*.28 (.15-.5).61 ( ).58 ( ).29 ( ).9 (.1-.71).3 (.8-1.1).5 ( ).84 ( ) P Value <

3 Percent of Follow-up Time Cumulative % With Event 8/3/215 START: Cancer Events With Immediate vs Deferred ART Cancer Event, n Immediate ART (n = 2326) Deferred ART (n = 2359) Total Kaposi s sarcoma 1 11 Lymphoma, NHL + HL 3 1 Prostate cancer 2 3 Lung cancer 2 2 Anal cancer 1 2 Cervical or testis cancer 1 2 Other types* Time to Cancer Event Rate/1 PY: immediate,.2; delayed,.56 HR (immediate vs delayed):.36 (95%CI:.19 to.66, P =.1) Months Deferred ART Immediate ART *Immediate ART: squamous cell carcinoma, plasma cell myeloma, bladder cancer, fibrosarcoma. Deferred ART: gastric adenocarcinoma, breast cancer, ureteric cancer, malignant melanoma, myeloid leukemia, thyroid cancer, leiomyosarcoma, liver cancer, squamous cell carcinoma of head and neck. N Engl J Med [Epub ahead of print]. Lundgren J, et al. IAS 215. Abstract MOSY32. START: Primary Endpoint Events By Latest CD4 Count Latest CD4 > 5 % of Primary Events Rate/1 PY Immediate ART 88% (37/42) Deferred ART 59% (57/96) Immediate ART No. of Pts with Events (Rates/1 PY) (4.7)(.8)(.4)(.6)(.6) Deferred ART No. of Pts with Events (Rates/1 PY) (1.8)(2.)(1.5)(.6)(1.1) Latest CD4+ Cell Count (cells/mm 3 ) TEMPRANO: Immediate or Deferred ART Initiation ± IPT for African Pts Randomized, controlled, unblinded, multicenter (Ivory Coast), 2 x 2 factorial HIV+ pts with CD4 < 8 who did not meet WHO criteria for initiating ART (N = 256) Immediate ART (n = 511) Immediate ART + IPT (n = 512) Deferred ART (n = 515) Deferred ART + IPT (n = 518) ART initiated after randomization. IPT = 3 mg daily isoniazid from 1-7 months after enrollment and terminated 7 months after enrollment. Deferred until meeting WHO criteria for initiating ART. Patients in treatment arms well-matched at baseline First-line ART primarily TDF/FTC + EFV (68%-71%) or TDF/FTC + LPV/r (22%-24%) Med. duration of follow-up: 29.9 mos TEMPRANO ANRS Study Group. N Engl J Med [Epub ahead of print] 3

4 Cumulative Probability of Death or Severe HIV-Related Illness (%) 8/3/215 TEMPRANO: Immediate vs Deferred ART Initiation and IPT Delivery for African Pts Month Probability Deferred ART 14.1% Deferred ART + IPT 8.8% Immediate ART 7.4% Immediate ART + IPT 5.7% Months From Randomization TEMPRANO ANRS Study Group. N Engl J Med [Epub ahead of print] When to Start: DHHS Guidelines, July 215 ART recommended for all HIV+ individuals to reduce risk of disease progression. Strength and evidence for recommendation vary by pretreatment CD4 count: CD4 35 CD CD4 >5 AI AI AI ART recommended for HIV-infected individuals for prevention of HIV transmission. Strength and evidence for recommendation vary by transmission risk: Perinatal transmission Heterosexual transmission All other risk groups AI AI AIII US DHHS Guidelines, July 215 The Initial Regimen 4

5 8/3/215 DHHS Guidelines, April 215: What to Start Recommended regimens Boosted PI based INSTI based Alternative regimens NNRTI based DRV/r + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + TDF/FTC DTG + ABC/3TC EFV/TDF/FTC RPV/TDF/FTC (VL <1,; CD4 >2) PI based ATV/c + TDF/FTC (CrCl >7) ATV/r + TDF/FTC (DRV/c or DRV/r) + ABC/3TC DRV/c + TDF/FTC (CrCl >7) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, April 215. Integrase Inhibitors ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) 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%) Lennox JL, et al. Ann Intern Med 214;161:

6 HIV-1 RNA < 5 c/ml (%) 8/3/215 ACTG 5257: Tolerability Failure Toxicity-Associated Discontinuation of randomized ART* ATV/r (N=65) RAL (N=63) DRV/r (N=61) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity Jaundice/Hyperbilirubinemia 47 Other hepatic toxicity Skin toxicity Metabolic toxicity 6 2 Renal toxicity (all nephrolithiasis) 4 Abnormal chem/heme (excl. LFTs) 2 Other toxicity *Participants allowed to switch therapy for intolerable toxicity Lennox JL, et al. Ann Intern Med 214;161: WAVES: EVG/COBI/TDF/FTC vs ATV/r + TDF/FTC in ART-Naive Women International, randomized, double-blind, phase III trial Wk 48 HIV+ women with VL 5 ; no previous ART; and egfr 7 ml/min (N = 575) EVG/COBI/TDF/FTC QD + Placebos for ATV, RTV, and TDF/FTC QD (n = 289) ATV/r + TDF/FTC QD + Placebo for EVG/COBI/TDF/FTC QD (n = 286) Openlabel extension Patients generally well-matched at baseline Patients with VL > 1,: EVG/COBI/TDF/FTC arm, 24%; ATV/r + TDF/FTC arm, 25% Squires K, et al. IAS 215. Abstract MOLBPE8. WAVES: Key Results EVG/COBI/TDF/FTC ATV/r + TDF/FTC n = Overall 1, > 1, VL) EVG/COBI/FTC/TDF ATV/RTV + TDF/FTC Emergent Resistance n = 289 n = 286 Resistance-associated population Developed resistance 3 mutations to study drugs No significant differences between arms Change from BL egfr, spine or hip BMD, LDL or HDL cholesterol, total cholesterol to HDL ratio, or triglycerides Significantly greater increase in total cholesterol with EVG/COBI/TDF/FTC Lower rate of discontinuations due to AEs with EVG/COBI/TDF/FTC vs ATV/r + TDF/FTC (2.4% vs 7.%) Squires K, et al. IAS 215. Abstract MOLBPE8. 6

7 Proportion (%) with <5 c/ml 8/3/215 SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC WK 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); p=.3 DTG+ABC/3TC: 88% EFV/TDF/FTC: 81% DTG 5 mg + ABC/3TC QD EFV/TDF/FTC QD BL Week DTG + ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1 o endpoint) Walmsley S, et al. N Engl J Med 213;369: Comparing the integrase inhibitors Agent Advantages Disadvantages Raltegravir Longest experience Fewest drug interactions Elvitegravir Single-tablet regimen (STR) Once-daily dosing Dolutegravir The only non-tdfcontaining STR Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RALand EVG-resistant virus Twice daily dosing (for now) No coformulation Requires COBI boosting COBI drug interactions similar to RTV Cofomulated only with ABC/3TC Together, 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. PIs 7

8 Percentage of Subjects (%) 8/3/215 GS 114: ATV/COBI vs. ATV/r with TDF/FTC Snapshot Weeks 48, 96, 144 (ITT) COBI (n=344) RTV (n=348) W48 W96 W144 W48 W96 W144 W48 W96 W144 95% CI for Difference Favors Favors ATV + RTV ATV + COBI W48 W96 W Virologic Success Virologic Failure No data * -12% 12% Mean CD4 cell increase (cells/mm 3 ) was 31 (COBI) vs 332 (RTV) * 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 Gallant JE, et al. ICAAC 214, Washington, DC. Abstract H ATV/cobi 3/15 mg once daily DRV/cobi 8/15 mg once daily Only for patients with no DRV resistance mutations NRTIs 8

9 % of those with given CVD risk receiving ABC 8/3/215 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 D:A:D 214 Use of ABC in cohort over time 35 D:A:D presentation March Low CVD risk Mod CVD risk High CVD risk CVD risk U/K Total cohort 5 RR (1.68, 2.33) RR 1.97 (1.43, 2.72) 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 = 1948) 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. Adjusted HRs for MI in Those With Recent ABC Use D:A:D Replication Full Study Restricted Study Recent ABC use significant in restricted population and D:A:D replication Significant predictors: Both: Age 6+, HTN, egfr < 3, AIDS Full: Smoking, DM 9

10 8/3/215 NRTI-Sparing Regimens NEAT 1: DRV/r + either RAL or TDF/FTC: Primary endpoint at W96 by baseline characteristics RAL + DRV/r TDF/FTC + DRV/r Overall n = % 13.7 % Baseline HIV-1 RNA < 1, c/ml n = % 7 % > 1, c/ml n = % 27 % p =.9 Baseline CD4+ < 2/mm 3 n = % 21.3 % > 2/mm 3 n = % 12.2 % p = Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted Raffi et al, CROI214, Abstract 84LB NRTI-sparing regimens Regimen DRV/r + RAL (ACTG ) DRV/r + RAL (NEAT 2 ) DRV/r + MVC (MODERN 3 ) ATV/r + RAL (HARNESS 4 switch) LPV/r + RAL (PROGRESS 5 ) LPV/r + EFV (ACTG ) LPV/r + 3TC (GARDEL 7 ) LPV/r + 3TC or FTC (OLE 8 switch) ATV/r + 3TC (SALT 9 switch) Results Poor performance at high VL Less effective at high VL, low CD4 Less effective than standard ART Less effective than standard ART Small study; few pts with high VL Poorly tolerated but effective As effective as standard ART As effective as standard ART As effective as standard ART 1. Taiwo B, et al. AIDS. 211;25: Raffi et al. CROI 214, Abstract 84LB 3. Stellbrink H-J, et al. IAD 214. Abstract MOAB11 4. Van Lunzen J et al. IAC 214. Abstract A Reynes J, et al. AIDS Res Hum Retroviruses. 213;29: Riddler SA, et al. N Engl J Med 28;358: Cahn P, et al. Lancet Infect Dis 214;14: Gatell J, et al. AIDS 214. Abstract LBPE Perez-Molina, J.A., et al. IAC 214. AbstractL BPE18. 1

11 VL < 5 c/ml by Snapshot Algorithm (%) 8/3/215 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 My choices: DRV/c + DTG + (3TC or FTC) DRV/c + ETR (+/- 3TC or FTC) DRV/c + (3TC or FTC)? LATTE: Virologic Success Through Maintenance Week 96 Induction Phase Maintenance Phase 84% 75% 68% 63% 4 CAB 1 mg (n = 6) CAB 3 mg (n = 6)* 2 CAB 6 mg (n = 61) EFV 6 mg (n = 62) BL Wks 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 Margolis D, et al. CROI 215. Abstract 554LB. *Cabotegravir 3 mg selected for future development At next year s conference, will anyone still talk about NRTI-sparing regimens? 11

12 Mean % Change From BL Mean (SD) Change from Baseline egfr* 8/3/215 Tenofovir alafenamide (TAF) Prodrug of tenofovir with lower TFV plasma concentrations, increased delivery to hepatocytes, lymphoid cells Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV Cathepsin A TFV-MP TFV-DP GS14/111: Significantly smaller decline in hip and spine BMD with TAF Smaller decline in hip and spine BMD with TAF TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) P <.1 2 P < Wk Wk n =845 n = Higher fasting lipids with TAF; TC:HDL ratio same [1] Sax P, et al. CROI 215. Abstract 143. TAF vs. TDF: Renal Safety 2 E/C/F/TAF E/C/F/TDF p < Time (Weeks) Events n (%) E/C/F/TAF n=866 E/C/F/TDF n=867 Renal adverse events leading to discontinuation 4 (.5) Tubulopathy/Fanconi syndrome Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, 215. Abst. 143LB. 12

13 Median % Change in BMD (Q1, Q3) Median % Change from Baseline (Q1, Q3) Wk 48 HVL < 5 % 8/3/215 TAF vs. TDF: Quantitative Proteinuria Urine [protein]:creatinine Ratio Protein (UPCR) Albumin (UACR) RBP Beta2- microglobulin E/C/F/TAF E/C/F/TDF p <.1 for all Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 11 μg/g 13 μg/g Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, 215. Abst. 143LB. Switch from TDF-based Regimens to E/C/F/TAF: Virologic Outcomes Primary Endpoint EVG/COBI/FTC/TAF TDF-Based Regimen P <.1 P =.2 P =.2 P = NS n/n = 932/ 444/ All Prior Regimens 241/ / / / 199 Prior Prior EFV/TDF/FTC Boosted ATV + TDF/FTC 31/ / 153 Prior EVG/COBI/ FTC/TDF Mills A, et al. IAS 215. Abstract TUAB12. Switch from TDF-based Regimens to E/C/F/TAF : Renal and Bone Outcomes Hip BMD was similarly increased for pts treated with TAF regimen EVG/COBI/FTC/TAF TDF-Based Regimen Baseline Week Week 48 P <.1 Regimen EVG/COBI/ FTC/TAF (n = 959) TDF-Based Regimen (n = 477) Renal Events Leading to Discontinuation Acute renal failure Interstitial nephritis Chronic kidney disease Elevated serum creatinine Fanconi syndrome (mild jaundice) Increased creatinine Nephretic colic (nephrolithiasis) Mills A, et al. IAS 215. Abstract TUAB12. 13

14 Median Change from Baseline Pts with HIV-1 RNA < 5 Copies/mL (%) Pts with HBV DNA <29 IU/mL* (%) Mean % Change Spine BMD 8/3/215 GS-112: Switching to E/C/F/TAF Regimen With Renal Impairment (egfr 3-6) Multicenter, open-label phase III trial, N=242 Changes in egfr from baseline to Wk Total TDF Non-TDF * * Changes in spinal BMD from baseline to Wk Total TDF Non-TDF 2.95* 2.29*.99-1 Baseline: *P <.5. egfr CG ml/min egfr CKD-EPI Cr ml/min/1.73m 2-2 *P <.5. Gupta S, et al. IAS 215. Abstract TUAB13. Switching Pts with HIV/HBV Coinfection to a TAF-Based Regimen International, multicenter, single-arm, open-label phase IIIb trial Pts with virologically suppressed HIV infection on any regimen, chronic HBV coinfection, and egfr > 5 ml/min switched to EVG/COBI/FTC/TAF for 48 wks (N = 72) Week 24 Week Significant improvement in median Wk 48 FibroTest score with switch (-.4, P =.18) Gallant J, et al. IAS 215. Abstract WELBPE13. EVG/COBI/TAF/FTC TAF/FTC RPV/TAF/FTC (DRV/COBI/TAF/FTC) 14

15 8/3/215 P7: Doravirine + TDF/FTC vs EFV + TDF/FTC in ART-Naive Pts Double-blind, randomized, phase 2 trial, N= DOR + TDF/FTC EFV + TDF/FTC % with VL < Treatment Wk NC=F approach. Most virologic failure was due to low-level viremia Virologic failure, VL 4: DOR, 15.7%; EFV, 1.2% Virologic failure, VL 2: DOR, 3.7%; EFV,.9% Gatell JM, et al. IAS 215. Abstract TUAB n/n = Response stratified by VL 1, c/ml / 66 54/ 63 % < 4 copies/ml DOR + TDF/FTC > 1, c/ml / 25/ % < 4 copies/ml EFV + TDF/FTC More in the pipeline Ibalizumab: entry inhibitor monoclonal antibody binds CD4 being studied for treatment and prevention BMS : entry inhibitor Blocks attachment by binding to gp12 BMS : maturation inhibitor Disrupts processing of gag protein Trial in naïve pts planned GS9883: integrase inhibitor Unboosted Potential for coformulation with TAF/FTC 1. Lalezari J et al. CROI 214, Abstract Hwang C et al. CROI 215, Abstract 114LB Switching and Simplifying Therapy in Suppressed Patients 15

16 8/3/215 Case: J.B. J.B. is a 63 year old man with longstanding HIV infection, diagnosed in 1987 He has been treated by multiple doctors on a variety of regimens since the early 9 s. He does not have old records and does not know his treatment history He remembers being told he has some resistance He is now on DRV/r (6/1 mg twice daily) + RAL + ETR + TDF/FTC He wants a simpler regimen, once-daily with fewer pills Switching Regimens Switching Regimens Rationale for switching with virologic suppression (DHHS) To simplify therapy (reduce pill burder, dosing frequency, improve adherence) To enhance tolerability, decrease short- and long-term toxicity To change food or fluid requirements To avoid parenteral administration (enfuvirtide) To minimize or address drug interactions To allow for optimal use of ART during or in event of pregnancy To reduce cost Other reasons (mine) To avoid embarrassment To prevent boredom DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, May

17 8/3/215 Recent Switch Studies: Suppressed Trial From To Outcome GS-123 TDF/FTC + RAL TDF/FTC/EVG/Cobi GS-264 TDF/FTC/EFV TDF/FTC/RPV Strategy-NNRTI TDF/FTC + NNRTI TDF/FTC/EVG/Cobi Strategy-PI TDF/FTC + PI/r TDF/FTC/EVG/Cobi SPIRIT 2 NRTI + PI/r TDF/FTC/RPV SPIRAL 2 NRTI + PI/r 2 NRTI + RAL SALT ATV/r + 2 NRTI ATV/r + 3TC OLE LPV/r + 2 NRTIs LPV/r + 3TC SWITHCMRK 2 NRTI + LPV/r 2 NRTI + RAL HARNESS 2 NRTI + 3 rd Agent ATV/r + RAL Slide adapted from David Wohl SWITCHMRK 1 & 2: From LPV/r + NRTIs to RAL + NRTIs Wk 12 lipid analysis Wk 24 efficacy analysis HIV+ pts with viral suppression on LPV/rbased ART for 3 mos. Not required to be initial regimen (N = 72) (SWITCHMRK 1: 348 SWITCHMRK 2: 354) Switch to RAL + other BL ARVs* (SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 176) Continue LPV/r + other BL ARVs* (SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 178) *All patients continued background regimen including 2 NRTIs. Eron JJ, et al. Lancet. 21;375: SWITCHMRK: Prior failure predicts failure Inferior efficacy of RAL driven by pts with previous virologic failure Outcome Patients without previous virologic failure SWITCHMRK1 SWITCHMRK 2 RAL (n = 174) LPV/r (n = 174) RAL (n = 176) LPV/r (n = 178) VL < 5 at Wk 24, % Treatment difference, % (95% CI) -.7 (-9.9 to 8.6) -1. (-8.5 to 6.3) Patients with previous virologic failure VL < 5 at Wk 24, % Treatment difference, % (95% CI) (-33. to -2.5) (-26.5 to -2.6) Eron JJ, et al. Lancet. 21;375:

18 Viral Load 8/3/215 Switching: Caveats Know the treatment and resistance history Avoid switching from high barrier to lower barrier agents when you don t Switching and simplifying therapy Horizontal Switches : switch to drug with equal or higher resistance barrier RTV COBI (boosters) Switches within INSTI class EFV or NVP RPV or ETR LPV/r or ATV/r DRV/r ABC or AZT TDF Anything boosted PI Vertical Switches : switch to drug with lower resistance barrier Most drug discontinuations Boosted PI NNRTI Boosted PI INSTI Boosted PI any STR DRV/r twice daily once daily Switching: Know what you need to know to maintain suppression Adapted from David Wohl Time 18

19 8/3/215 Case: J.B. J.B. is a 63 year old man with longstanding HIV infection, diagnosed in 1987 He has been treated by multiple doctors on a variety of regimens since the early 9 s. He does not have old records and does not know his treatment history He remembers being told he has some resistance He is now on DRV/r (6/1 mg bid) + RAL (4 mg bid) + ETR (2 mg bid) + TDF/FTC He requests a simpler regimen, once-daily with fewer pills Options for J.B.: The good, the bad, and the iffy Switch OK? Comments RAL DTG Yes Reduces pill burden DTG superior in ART-exp d pts (SALING) ETR 2 bid 4 QD Yes Not approved dose but supported by PK Discontinue TDF/FTC Maybe NRTIs unnecessary if >2 fully active agents (OPTIONS) His complex salvage regimen suggests that he probably has TDF and FTC resistance already DRV/r BID QD Risky DRV mutations? (V11I, V32I, L33F, I47V, I5V, I54L, I54M, T74P, L76V, I84V, L89V) APV and FPV most likely to cause DRV crossresistance Change to ABC/3TC/DTG Risky DTG resistance barrier may be as high as a boosted PI NRTI resistance unknown Change to any other STR No way! Remember SWITCHMRK! Provides drug resistance data when standard resistance testing cannot be performed due to inadequate plasma viral load. Interrogates the viral archive [amplifies cell-associated proviral DNA] using next-generation sequencing methods to provide a list of the archived mutations. 19

20 8/3/215 How to Choose? (My personal recommendations) No comorbidities or interacting medications: DTG/ABC/3TC EVG/COBI/FTC/TDF High cardiac risk: DTG + TDF/FTC EVG/COBI/FTC/TDF Kidney disease (low cardiac risk): DTG/ABC/3TC (expect fall in egfr) RAL + ABC/3TC RTV or COBI interactions: DTG/ABC/3TC DTG + TDF/FTC RAL + TDF/FTC How to Choose? (My personal recommendations) Side effects or desire for simplification on a suppressive regimen: EVG/COBI/TDF/FTC RPV/TDF/FTC DTG/ABC/3TC (no switch data yet, but why not?) Known or predicted non-adherence: DRV/c + TDF/FTC DTG/ABC/3TC (?) Likelihood of pregnancy: ATV/r + TDF/FTC HCV coinfeciton: RAL + TDF/FTC DTG/ABC/3TC (or TDF/FTC) 2