4/14/2016. Breaking News From the 2016 Conference on Retroviruses and Opportunistic Infections

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1 Breaking News From the 2016 Conference on Retroviruses and Opportunistic Infections 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 FINAL: 03/29/16 Atlanta, Georgia: April 8, 2016 Financial Relationships With Commercial Entities Dr Lennox has served as a consultant or advisor to Bristol-Myers Squibb and Merck & Co, Inc. (Updated 04/8/16) Slide 2 of 38 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. Slide 3 of 38 1

2 Populations and Outcomes Slide 4 of 38 Slide 5 of 38 HIV+ vs. HIV- Life Expectancy- Kaiser California 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 Life Expectancy Much Improved, But Gaps Remain Slide 6 of 38 2

3 Effect of Race, Gender and Other Factors on Success on Initial ART A5257:1809 ARV naïve began TDF/FTC + RAL or DRV/r or ATV/r 24% women; 43% Black, 22% Hispanic Slide 7 of 38 Ribaudo H #476 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) Slide 8 of 38 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. Slide 9 of 38 3

4 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 longacting injectable ART 4. Some other intervention 19% 53% 17% 11% Slide 10 of 38 Improving Substance Users ART Outcome CTN 0049 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 Slide 11 of 38 CTN 0049 Results- Pay me now and pay me later? Slide 12 of 38 Change in Viral Suppression % p = p = mo. 12 mo. At 6 months engagement in care was also improved Southern sites had much higher rates of virologic failure (p<0.0001)

5 Treatment Naïve Studies and New ARVs Slide 13 of 38 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 Slide 14 of 38 Margolis DA # 31LB LATTE Results Rilpivirine did not achieve desired plasma levels until ~ week 16, methods to increase early levels being explored No new ART resistance detected Slide 15 of 38 5

6 Adverse Events and Labs Maintenance Period 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) Slide 16 of 38 Q 8Wk IM Q 4Wk IM Number of injections Number of ISRs Grades Grade (80%) 1021 (83%) Grade (19%) 197 (16%) Grade 3 Duration, days 12 (1%) 10 (<1%) Median Slide 17 of 38 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 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% Slide 18 of 38 Gatell #470 6

7 Doravirine vs. EFV Results Doravirine 100mg QD had similar efficacy to EFV, both with TDF/FTC AEs % DOR EFV Nightmares Dizziness Grade 1 LDL > Grade 2 TG Gatell JM #470 Slide 19 of 38 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 Slide 20 of 38 ¹ Michailidis E Retrovirology 2015 ² Friedman EJ #437LB Switch Study Slide 21 of 38 7

8 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. Slide 22 of 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 What do you recommend? 7% 66% 27% Slide 23 of 38 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 Gallant J # 29 Slide 24 of 38 8

9 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 Slide 25 of 38 End Organ Disease Slide 26 of 38 Body Composition Changes: RAL vs. TDF/FTC Neat 001study- DRV/r + TDF/FTC vs. DRV/r + RAL DEXA Substudy of 126 pts Week 96 DRV/r + RAL DRV/r + TDF/FTC Limb Fat Change +9.8% +4.9% 20% Limb Fat 10.4% 17.9% Body Fat Change +15.8% +6.0% 20% Trunk Fat 40.8% 35.7% Bernardino J #45 Slide 27 of 38 9

10 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 Slide 28 of 38 Borges AH #46 Slide 29 of 38 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 Siberry G #36 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 Switch Study TAF Quad Switch Substudy ² BMD spine and hip Slide 30 of 38 ¹ Grant R #48LB ² Gallant J #29 10

11 Bisphosphonate to Prevent ART-Associated Bone Loss 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 Ofotokun I #47 Slide 31 of 38 Single Dose Zoledronic Acid Preserves BMD Lumbar Spine Hip Femoral Neck Slide 32 of 38 Prevention Slide 33 of 38 11

12 Maraviroc as PrEP A5305/HPTN 069 Double-blind, randomized study where all pts got 3 pills daily ¹ 404 MSM/TGW enrolled and treated MVC MVC+FTC MVC+TDF TDF+FTC New HIV 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 Slide 34 of 38 ¹ Gulick R #103 ² McGowan #104 Cabotegravir as PrEP Phase 2A - Safety and PK (ECLAIR) Placebo-controlled, 4 week oral CAB 30mg or PBO; then Q/2 wk IM CAB 800mg or PBO 127 low risk MSM enrolled Slide 35 of 38 PBO CAB % I.S. pain % Grade 3 pain 0 10 # days pain 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 Dapivirine Ring PrEP-Phase III Trials 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 Slide 36 of 38 ¹ Baeten JM #109LB ² Nel A #110LB 12

13 DPV Ring Efficacy Phase III Trials MTN 020 IPM 027 DPV PBO DPV PBO % 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 Slide 37 of 38 MTN 020 Adherence and Age Slide 38 of 38 Opportunistic Infections Slide 39 of 38 13

14 Operational Research for Cryptococcal Antigen Screening (ORCAS) Trial 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<50 or CRAG>1:160 Slide 40 of 38 Morawski BM #