Jeffrey L. Lennox, MD Professor of Medicine Associate Dean for Clinical Research Emory University School of Medicine Medicine Chief of Service Grady Health Systems Atlanta, Georgia Breaking News From the 2016 Conference on Retroviruses and Opportunistic Infections FINAL: 03/29/16 Atlanta, Georgia: April 8, 2016 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 2 of 39 Learning Objectives After attending this presentation, participants will be able to describe the results of studies presented at CROI 2016, including on: Results of studies of new drugs, combinations, and formulations. Risks and possible treatments for antiretroviral therapy (ART)-associated bone loss Approaches to prevent HIV-infection. From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 3 of 39 Populations and Outcomes From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 4 of 39 Adults receiving care at Kaiser California, HIV- to HIV+ 10:1 match for those seen between ,768 HIV+, 257,600 HIV-, 91% male, ~25% white, ~35% ever smoked Marcus JL #54 HIV+ vs. HIV- Life Expectancy- Kaiser California From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 5 of 39 Life Expectancy – Much Improved, But Gaps Remain From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 6 of 39 A5257:1809 ARV naïve began TDF/FTC + RAL or DRV/r or ATV/r 24% women; 43% Black, 22% Hispanic Ribaudo H #476 Effect of Race, Gender and Other Factors on Success on Initial ART From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 7 of 39 Association of Sex and Race/Ethnicity with V.F. – Adjusting for Other Factors Women did no worse than men, and Hispanics no worse than non-Hispanic whites, after adjusting for race (Women) and income (Hispanics) From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 8 of 39 Case 1 A 22 year old male, high-school drop out diagnosed 1 year ago, CD4 = 2 (1%). Has been hospitalized 5 times for wasting, PCP, diarrhea. Continues to use marijuana, crack and ETOH. Has never gone to clinic. Social work has referred him to a drug rehabilitation program. From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 9 of 39 Which of these do you think will most effectively engage him in ART? 1.A healthcare navigator 2.A navigator plus cash incentives 3.Enroll in a trial of long- acting injectable ART 4.Some other intervention From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 10 of 39 Hospitalized, viremic pts in 11 hospitals randomized to 11 sessions of patient navigation (PN), vs PN + $, vs usual care PN+$ pts can earn up to $1160 total- $180 for 4 clinic visits, $100 for VL<50 Metsch L #27 Improving Substance Users ART Outcome– CTN 0049 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 11 of 39 At 6 months engagement in care was also improved Southern sites had much higher rates of virologic failure (p<0.0001) p = 0.04 p = 0.68 CTN 0049 Results- Pay me now and pay me later? From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 12 of 39 Treatment Naïve Studies and New ARVs From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 13 of 39 Margolis DA # 31LB Oral Induction, Injection Maintenance- LATTE week 32 Cabotegravir is a new integrase inhibitor. Population- ART naïve patients with mean CD4 489, 18% with HIV RNA >100,000K Volume– two 3mL injections q8 weeks or two 2mL injections q4 weeks From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 14 of 39 LATTE Results Rilpivirine did not achieve desired plasma levels until ~ week 16, methods to increase early levels being explored No new ART resistance detected From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 15 of 39 Number of subjects reporting ISRs decreased over time, from 86% (Day 1) to 33% (Week 32) 2/230 subjects (1%) withdrew as result of injection reactions (Q 8 Wk) Adverse Events and Labs—Maintenance Period Q 8Wk IM Q 4Wk IM Number of injections Number of ISRs Grades Grade 1839 (80%)1021 (83%) Grade 2202 (19%)197 (16%) Grade 312 (1%)10 (<1%) Duration, days Median3.0 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 16 of 39 Efficacy and Safety of ELV/c/TAF/FTC in Adolescents Open label, 48 week, single arm study of ELV/c/TAF/FTC Age yrs, CD4>100, Wt>35kg 48 Subjects followed to 48 wks 92% (48/50) HIV RNA <50c/mL at 48 wks In this small study there were no signs of renal tubular dysfunction Gaur #817 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 17 of 39 Gatell #470 New NNRTI Doravirine vs. EFV- Week 48 Results Doravirine active in vitro against K103N, Y181C, G190A, E138K Metabolized by Cyp3A4, but not an inducer or inhibitor Continuation of 100mg from a dose ranging study, plus new 100mg pts, vs. EFV in treatment naïve; with TDF/FTC 92% male, CD4 ~400, VL>100,000 ~36% From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 18 of 39 Doravirine vs. EFV Results Doravirine 100mg QD had similar efficacy to EFV, both with TDF/FTC AEs %DOREFV Nightmares Dizziness ≥ Grade 1 LDL > Grade 2 TG01.9 Gatell JM #470 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 19 of 39 ² Friedman EJ #437LB ¹ Michailidis E Retrovirology 2015 Long Acting Nucleoside Analog – Potential Once Weekly Dosing EFdA (MK-8591) in vitro is active against HIV, including K65R TDF resistant ¹ MK mg single dose in 6 ARV-naïve patients ² PBMC MK-8591-TP concentrations exceeded target at 7 days 6/6 pts developed headaches From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 20 of 39 Switch Study From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 21 of 39 Case 2 A 28 year old Black female on chronic ART with ELV/c/TDF/FTC. Viral load is suppressed, eGFR is normal. She heard through a friend that she should switch to a TAF-containing regimen. From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 22 of 39 What do you recommend? 1. There is not enough data on efficacy in this population, stay the course 2. Change TDF to TAF since it is effective and less toxic 3. Wait until we have more safety data on long-term, TAF treated patients From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 23 of 39 Gallant J # 29 Switching Patients From TDF/FTC to TAF/FTC Stable patients on ART entered a placebo-controlled study to change TDF to TAF, or remain on TDF TAF/FTC dosage differs: 200/10 mg with PI, 200/25 mg with non-PI From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 24 of 39 TAF Switch- Safety Tolerability and A/E similar Grade 3 or 4 LDL in 20 pts on TAF, 8 pts on TDF Emergent resistance in 1 pt (184V) on TAF From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 25 of 39 End Organ Disease From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 26 of 39 Week 96DRV/r + RALDRV/r + TDF/FTC Limb Fat Change+9.8%+4.9% ≥ 20% ↓ Limb Fat10.4%17.9% Body Fat Change+15.8%+6.0% ≥ 20% ↑ Trunk Fat40.8%35.7% Body Composition Changes: RAL vs. TDF/FTC Neat 001study- DRV/r + TDF/FTC vs. DRV/r + RAL DEXA Substudy of 126 pts Bernardino J #45 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 27 of 39 Borges AH #46 Bone Fractures and Osteonecrosis – A Multi-National Risk Analysis EUROSIDA cohort of 11,820 patients with 86,118 PYFU since Jan New Fractures – 619, rate 7.2/1,000 PYFU Osteonecrosis – 89, rate 1.0/1,000 PYFU Patients who ever used TDF were more likely (IRR 1.40) to develop fractures, but Not osteoporotic fractures From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 28 of 39 Siberry G #36 Maternal TDF – Effect on Infant Bone? DXA substudy of PROMISE: Maternal ZDV + sdNVP vs ZDV/3TC + LPV/r vs TDF/FTC + LPV/r About 120 infants per arm DXA scanned after birth No difference in LS between arms. Whole body BMC was lower in both triple drug arms From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 29 of 39 ¹ Grant R #48LB² Gallant J #29 Stopping or Changing TDF – Effect on Bone Follow on study of IPREX: 352 pts with DEXA at 24 weeks after D/C TDF/FTC PrEP ¹ − Annualized BMD ↑1.13 hip, 1.81 spine TAF Quad Switch Substudy ² − ↑BMD spine and hip TAF Switch Study From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 30 of 39 ART naïve began TDF/FTC + ATV/r plus either Zoledronic acid 5mg IV or placebo IV single dose BMD at baseline, q 24 weeks 63 subjects completed 48 wks −79% male, 84% Black, CD4 ~ 125 CTx, a marker of bone resorption, was dramatically reduced in the ZA arm Bisphosphonate to Prevent ART-Associated Bone Loss Ofotokun I #47 From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 31 of 39 Single Dose Zoledronic Acid Preserves BMD Lumbar Spine HipFemoral Neck From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 32 of 39 Prevention From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 33 of 39 ¹ Gulick R #103² McGowan #104 MVCMVC+FTCMVC+TDFTDF+FTC New HIV+4010 Maraviroc as PrEP – A5305/HPTN 069 Double-blind, randomized study where all pts got 3 pills daily ¹ 404 MSM/TGW enrolled and treated Of 5 newly HIV +, all had R5 HIV, 2/5 never had detectable drug levels and 3/5 had low levels Rectal biopsy tissue explants from MVC only patients more easily infected in vitro than tissues from patients in other arms ² From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 34 of 39 PBOCAB % I.S. pain2792 % ≥ Grade 3 pain010 # days pain205.4 Placebo-controlled, 4 week oral CAB 30mg or PBO; then Q/2 wk IM CAB 800mg or PBO 127 low risk MSM enrolled PK showed higher peaks, lower trough than expected. 2 new HIV+, 1 PBO + 1 CAB. CAB pt had low PK levels despite I.M. injections. Markowitz M #106 Cabotegravir as PrEP Phase 2A - Safety and PK (ECLAIR) From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 35 of 39 ¹ MTN 020 (Aspire) enrolled 2,629 women at 4 African sites. −1:1 randomization to DPV ring vs. control ring changed monthly −Residual drug concentration of returned, used rings were measured ² IPM027 enrolled 1,959 African women −2:1 randomization ¹ Baeten JM #109LB² Nel A #110LB Dapivirine Ring PrEP-Phase III Trials From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 36 of 39 MTN 020IPM 027 DPVPBODPVPBO% Efficacy MTN / IPM Rate/100 Pt / 31 Rate, Age > / 37 Rate, Age ≤ <0 / 15 %NNRTI Resistance n/a Higher residual drug concentration in used rings correlated with decreased protection DPV Ring Efficacy – Phase III Trials From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 37 of 39 MTN 020 – Adherence and Age From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 38 of 39 Opportunistic Infections From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

Slide 39 of 39 Test WHO recommended therapy for asymptomatic + CRAG 151 asymptomatic CRAG+ given Fluconazole 800mg QD x 2 wks→Add ART→400mg QD x 8 wks ~25% risk for death and/or meningitis, risk greater if CD4 1:160 Morawski BM # 159 Operational Research for Cryptococcal Antigen Screening (ORCAS) Trial From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.