1. Joel E. Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Clinical Professor of Medicine University of New Mexico School of Medicine Albuquerque, New Mexico Starting and Switching: Modern Day Antiretroviral Dilemmas; A Case-Based, Panel Discussion New York, New York: March 23, 2016 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.

2. Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, New Mexico Johns Hopkins University School of Medicine University of New Mexico ART Strategies From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.

3. Slide 3 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Learning Objectives After attending this presentation, participants will be able to: Describe the approach to NRTI selection in patients with kidney disease and/or cardiac risk factors Discuss the use of PrEP in patients with ongoing high- risk behavior Discuss the approach to simplification of ART in treatment-experienced patients with uknown treatment histories

4. Slide 4 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. T.M.  T.M. is a 48-year-old man with HIV infection.  His viral load has been suppressed for the last 6 years, CD4 in 700’s, first on TDF/FTC + DRV/r (then DRV/c in 1/15)  Baseline genotype: no mutations. PI chosen because of his concern about EFV side effects  Creatinine rose gradually from 1.02 to 1.52 (eGFR 52)  He had 1+ proteinuria and 1+ urine glucose (normal plasma glucose) with a normal serum phos, but FEphos of 25%  HLA B*5701 was negative, and he was switched from TDF/FTC to ABC/3TC 1 year ago

5. Slide 5 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. T.M.  He takes atorvastatin for hypercholesterolemia  He smokes 1 ppd  He takes losartan/HCTZ for hypertension  His brother and father had MIs in their early 50’s  HbA1C and fasting glucose are consistently normal  Creatinine is now 1.25  He still has 1+ proteinuria, but no longer has glycosuria  FEphos is now 12% (normal serum phos)

6. Slide 6 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. T.M. What would you recommend? 1. Make no changes 2. Change ABC/3TC to TAF/FTC 3. Change DRV/c to an integrase inhibitor 4. Discontinue ABC and leave him on DRV/c + 3TC 5. 2 and 3 6. Something else

7. Slide 7 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. TAF vs. TDF: Quantitative Proteinuria Median % Change from Baseline (Q1, Q3) Protein (UPCR) Albumin (UACR) RBP Beta2- microglobulin p <0.001 for all Urine [protein]:Creatinine Ratio 76133168 57 E/C/F/TAF E/C/F/TDF Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, 2015. Abst. 143LB. Protein (UPCR) Albumin (UACR) RBP

8. Slide 8 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. OLE: Switching Suppressed Pts to LPV/r + 3TC Noninferior to Triple ART at Wk 48  New grade 3-4 AEs in 9 pts in each arm  Numerically greater increases in lipids, decreases in creatinine in triple-ART arm  VF in 3 pts in each arm –1 pt (dual-ART) tested for resistance; had K103N and M184V Patients (%) 91.5 90.9 Δ -0.6% (95% CI: -6.9% to 8.1%) Dual ART (n = 118) Triple ART (n = 121) 0 20 40 60 80 100 2.5 0.8 3.3 n = Therapeutic Response* Virologic Failure D/C Due to AE D/C for Other Reasons 5.1 3.3 *VL < 50 c/mL at Wk 48 (mITT). Gatell J, et al. AIDS 2014. Abstract LBPE17.

9. Slide 9 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. P.T.  P.T. is a 28-year-old, asymptomatic HIV-negative man requesting PrEP  He has an HIV-positive partner whose viral load is consistently suppressed on ART  He sometimes has sex with other partners of unknown HIV status. He uses condoms “sometimes” for receptive anal sex  He was treated for secondary syphilis 6 months ago  A 4 th generation HIV test is negative. He has a negative HBsAg and normal renal function.  He had unprotected receptive anal sex with a partner of unknown status 1 week ago

10. Slide 10 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. What do you do with P.T.? 1.Start PrEP now 2.Order an HIV viral load, and start PrEP if it’s negative 3.Ask him to return for another rapid HIV test after at least two weeks without any potential exposure 4.Start PEP, with potential for transition to PrEP 5.Tell him he can start PrEP if he agrees to use condoms consistently 6.Discuss the virtues of abstinence and monogamy

11. Slide 11 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.

12. Slide 12 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. P.T.  He had a negative HIV RNA and was started on PrEP.  He returns for his 3-month follow-up visit and wants to continue.  Routine STD screening reveals asymptomatic rectal and pharyngeal gonorrhea and rectal chlamydia

13. Slide 13 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. In addition to treating his STDs, checking for HCV, and discussing treatment of his partners, what do you do with P.T. now? 1.Tell him you can’t renew PrEP if he continues to engage in unsafe sex 2.Talk to him about STD prevention, while quietly whispering under your breath “Thank God I put him on PrEP!”

14. 14  Of 2499 men, 360 (14.4%) RPR+ at screening; 333 (92.5%) confirmed  Syphilis incidence during trial: 7.3 cases/100 p-y No difference between study arms  HIV incidence varied by incident syphilis - 2.8 cases /100 p-y (no syphilis) vs 8.0 (syphilis) Hazard ratio 2.6 (95% CI, 1.6–4.4; P <.001) Clinical Infect Dis, 2014 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.

15. Slide 15 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.  2805 men with syphilis (11,714 p-y of follow-up)  423 (15%) acquired HIV  Annual incidence 3.6%  Risk factors (incidence): –MSM (5.6%) –Secondary syphilis (4.1%) –Additional bacterial STD after syphilis (7.9%)

16. Slide 16 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. D.T.  D.T. is a 65-year-old man with HIV infection who has been doing well for several years on TDF/FTC + DRV/r (600/100 mg bid) + RAL + ETR, with an HIV RNA <20 and CD4 763  He started ART in the late 80’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 wants to switch to a once-daily regimen, with as few pills as possible (preferably one)

17. Slide 17 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. What do you recommend? 1.EVG/COBI/FTC/TAF 2.RPV/FTC/TAF 3.DTG/ABC/3TC 4.EFV/TDF/FTC 5.I would not recommend a single-tablet regimen, but I would simplify his regimen in other ways 6.I would order a proviral DNA genotype 7.I would congratulate him on being alive and tell him to count his blessings and suck it up

18. Slide 18 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. You decide to simplify his regimen. What would you do with his RAL (400 mg bid)? 1. Discontinue it 2. Leave it alone 3. Change to RAL 800 mg once daily 4. Change to DTG 50 mg once daily 5. Change to DTG 50 mg twice daily 6. Change to an EVG/COBI-based regimen

19. Slide 19 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. What would you do with his ETR (200 mg bid)? 1. Discontinue it 2. Leave it alone 3. Change to ETR 400 mg once daily 4. Change to RPV

20. Slide 20 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. What would you do with his DRV/r (600/100 mg bid)? 1. Discontinue it 2. Leave it alone 3. Change to DRV/r 800/100 mg once daily 4. Change to DRV/c 800/150 mg once daily 5. Change to DRV/c 800/150 mg bid 6. Base decision on proviral DNA genotype

21. Slide 21 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. What would you do with his FTC/TDF 1. Discontinue it 2. Leave it alone 3. Change to FTC/TAF 4. Base decision on proviral DNA genotype

22. Slide 22 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Recent switch studies in suppressed pts TrialFromToOutcome GS-123 TDF/FTC + RALEVG/COBI/FTC/TDF ✔ GS-264 TDF/FTC/EFVRPV/FTC/TDF ✔ Strategy-NNRTI TDF/FTC + NNRTIEVG/COBI/FTC/TDF ✔ Strategy-PI TDF/FTC + PI/rEVG/COBI/FTC/TDF ✔ SPIRIT 2 NRTI + PI/rRPV/FTC/TDF ✔ SPIRAL 2 NRTI + PI/r (exp’d pts)2 NRTI + RAL ✔ SALT ATV/r + 2 NRTIATV/r + 3TC ✔ OLE LPV/r + 2 NRTIsLPV/r + 3TC ✔ GS-109 TDF-based ARTEVG/COBI/FTC/TAF ✔ STRIIVING Suppressive ARTDTG/ABC/3TC ✔ ATLAS-M ATV/r + 2 NRTIsATV/r + 3TC ✔ GS-119 “Salvage regimen”EVG/COBI/FTC/TAF + DRV ✔ LATTE CAB or EFV + 2 NRTIsCAB + RPV ✔ GS-1089 TDF/FTC + 3 rd agentTAF/FTC + 3 rd agent ✔ SWITCHMRK 2 NRTI + LPV/r (exp’d pts)2 NRTI + RAL ✗ HARNESS 2 NRTI + 3 rd AgentATV/r + RAL ✗ Adapted from David Wohl

23. Slide 23 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. HIV+ pts with viral suppression on LPV/r-based ART for ≥ 3 mos. Not required to be initial regimen (N = 702) (SWITCHMRK 1: 348 SWITCHMRK 2: 354) SWITCHMRK 1 & 2: From LPV/r + NRTIs to RAL + NRTIs 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) Wk 12 lipid analysis Wk 24 efficacy analysis *All patients continued background regimen including ≥ 2 NRTIs. Eron JJ, et al. Lancet. 2010;375:396-407.

24. Slide 24 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. SWITCHMRK: Prior failure predicts failure Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure Eron JJ, et al. Lancet. 2010;375:396-407. Outcome SWITCHMRK1SWITCHMRK 2 RAL (n = 174) LPV/r (n = 174) RAL (n = 176) LPV/r (n = 178) Patients without previous virologic failure  VL < 50 at Wk 24, %85.185.892.593.5  Treatment difference, % (95% CI)-0.7 (-9.9 to 8.6)-1.0 (-8.5 to 6.3) Patients with previous virologic failure  VL < 50 at Wk 24, %72.389.779.793.8  Treatment difference, % (95% CI)-17.3 (-33.0 to -2.5)-14.2 (-26.5 to -2.6)

25. Slide 25 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Switching: Caveats  Know the treatment and resistance history  Avoid switching from high barrier to lower barrier agents when you don’t

26. Slide 26 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Toma J, et al. ICAAC 2015, September 17-21, 2015, San Diego. 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%.

27. Slide 27 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. A.R.  A.R. is a 35-year-old woman who was diagnosed 5 years ago. She has had multiple hospitalizations for HIV- and substance abuse-related problems, but has never kept a follow-up appointment in the HIV clinic. She has never taken ART.  She has a history of depression and bipolar disorder but has been erratic with psychiatric follow-up and is currently on no psychiatric medications. She admits to depression.  CD4 count is 35; viral load is 213,000. Baseline genotype: wild-type

28. Slide 28 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. A.R.  She now comes to clinic for a new patient appointment, 1 week after hospitalization for PCP.  She is taking TMP/SMX and azithromycin prescribed at discharge.  She continues to use crack cocaine several times a week but denies active injection drug use.  She knows several people who have died of AIDS and wants to start ART, preferably with something “easy.”  You start her on a previously prescribed mood stabilizer and antidepressant and refer her to a psychiatrist, an adherence counselor, and substance abuse treatment.

29. Slide 29 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. A.R. What do you do about ART? 1. Start ART on this visit 2. Start ART if she returns to the clinic in 2-4 weeks 3. Start ART after her psychiatrist, adherence counselor, and substance abuse counselor feel she is ready 4. Start ART when the moon and planets line up 10

30. Slide 30 of 30 From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. When you do start ART, what 3rd agent will you use in addition to 2 NRTIs? 1. RPV 2. EFV 3. EVG/COBI 4. DRV/r 5. DRV/c 6. DTG 10