1. CCO Independent Conference Coverage* of the 2016 Conference on Retroviruses and Opportunistic Infections February 22-25, 2016 Boston, Massachusetts Clinical Impact of New Data From CROI 2016 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by independent educational grants from ViiV Healthcare (Major Supporter) and Merck.

2. Slide credit: clinicaloptions.comclinicaloptions.com About These Slides  Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients  When using our slides, please retain the source attribution:  These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for detailspermissions@clinicaloptions.com

3. Faculty Joel E. Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland Charles B. Hicks, MD Professor of Clinical Medicine Director, Owen Clinic University of California, San Diego San Diego, California

4. Disclosures Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo, and ViiV. Charles B. Hicks, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV.

5. Prevention

6. BMD Substudy of iPrEx: TDF/FTC PrEP vs Placebo in HIV-Neg High-Risk MSM/TGW  iPrEx: double-blind, randomized trial (N = 2499): 44% relative reduction in cumulative HIV risk with TDF/FTC vs PBO (P =.005) [1]  iPrEx DXA BMD substudy (N = 498) [2] : –Small net decrease in spine (-0.91%) and total hip (-0.61%) BMD with TDF/FTC vs PBO at Wk 24 (P =.001 for both); no difference in fracture rate between groups (P =.62)  Current analysis evaluated BMD changes after PrEP stop visit [3] Slide credit: clinicaloptions.comclinicaloptions.com 1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Mulligan K, et al. Clin Infect Dis. 2015;61:572-580. 3. Grant R, et al. CROI 2016. Abstract 48LB. DXA: iPrEx RCT Median: 1.2 yrs PrEP Gap Median: 1.5 yrs iPrEx OLE 1.4 yrs BLEvery 24 Wks PrEP d/c 6 Mos Post d/c OLE Enroll …

7.  Data compared for TFV-DP < or ≥ 16 fmol/M viable PBMC, concentration associated with 90% reduction in HIV infection risk in MSM/TGW Slide credit: clinicaloptions.comclinicaloptions.com Grant R, et al. CROI 2016. Abstract 48LB. *P <.001; † P <.05 Change in BMD From iPrEx Enrollment (%) SpineHip BLWk 24D/c6-Mos Post d/c OLE Enroll BLWk 24D/c6-Mos Post d/c OLE Enroll 2.0 1.5 1.0 0.5 0 -0.5 -1.5 2.0 1.5 1.0 0.5 0 -0.5 -1.5 3.0 2.0 1.0 0 -2.0 -3.0 3.0 2.0 1.0 0 -2.0 -3.0 Age < 25 Yrs Placebo Wk 24 TFV-DP < 16 Wk 24 TFV-DP ≥ 16 Age ≥ 25 Yrs Age < 25 Yrs Age ≥ 25 Yrs * * * † * * BMD Substudy of iPrEx: BMD Recovery After Discontinuation of TDF/FTC PrEP

8. Case Report: Multiclass Resistant HIV Infection Despite High Adherence to PrEP  43-yr-old MSM acquired multiclass resistant HIV-1 infection following 24 mos of oral once-daily TDF/FTC PrEP  Pharmacy records, blood concentration analyses, and clinical history support recent and long-term adherence to PrEP  PrEP failure likely result of exposure to PrEP-resistant, multiclass resistant HIV-1 strain Knox DC, et al. CROI 2016. Abstract 169aLB. Drug Class Mutations Detected on Day 7 Following p24-Positive Test Estimated Fold-Change in IC 50 or Change in Response (Drug) NRTI41L, 67G, 69D, 70R, 184V, 215E 1.9x (ABC), 61x (3TC), 38x (FTC), 1.3x (TDF) NNRTI181C43x (NVP) PI10INo relevant change INSTI51Y, 92Q Reduced (RAL), resistant (EVG), reduced (DTG) Slide credit: clinicaloptions.comclinicaloptions.com

9. MTN-020/ASPIRE & IPM-027: Dapivirine Vaginal Ring for HIV Prevention in Women  Silicone elastomer vaginal matrix ring containing NNRTI dapivirine 25 mg; ring replaced every 4 wks  Randomized, double-blind phase III trials –MTN-020/ASPIRE [1,2] : Malawi, South Africa, Uganda, Zimbabwe –IPM-027 (The Ring Study) [3] : South Africa, Uganda –Primary endpoints: efficacy and safety 1. Baeten JM, et al. CROI 2016. Abstract 109LB. 2. Baeten JM, et al. N Engl J Med. 2016;[Epub ahead of print]. 3. Nel A, et al. CROI 2016. Abstract 110LB. Dapivirine 25 mg Vaginal Ring every 4 wks + HIV Prevention Service Package (ASPIRE: n = 1313; IPM-027: n = 1300) Placebo Vaginal Ring every 4 wks + HIV Prevention Service Package (ASPIRE: n = 1316; IPM-027: n = 650) Sexually active HIV-uninfected adult women (ASPIRE: N = 2629; IPM-027: N = 1959) ≥ 1 yr; endpoint- driven duration Slide credit: clinicaloptions.comclinicaloptions.com

10. MTN-020/ASPIRE & IPM-027: Efficacy and Safety of Dapivirine Vaginal Ring  Efficacy for HIV prevention similar in both studies  No clinically relevant safety differences between arms *Excludes 2 sites with low adherence. 1. Baeten JM, et al. CROI 2016. Abstract 109LB. 2. Baeten JM, et al. N Engl J Med. 2016;[Epub ahead of print]. 3. Nel A, et al. CROI 2016. Abstract 110LB. Outcome ASPIRE [1,2] : 15 SitesASPIRE [1,2] : 13 Sites*The Ring Study [3] Dapivirine (n = 1308) Placebo (n = 1306) Dapivirine (n = 1198) Placebo (n = 1197) Dapivirine (n = 1300) Placebo (n = 650) HIV infections, n719754857756 HIV incidence (per 100 PYs) 3.34.52.84.44.16.1 HIV protection efficacy, % 27 (P =.046)37 (P =.007)31 (P =.040)  Among women older than 21 yrs -56 (P <.001)37 (P =.10) Slide credit: clinicaloptions.comclinicaloptions.com

11. ÉCLAIR: Cabotegravir LA in HIV-Negative Men at Low Risk for HIV Infection  Cabotegravir: potent INSTI formulated as oral tablet and for LA IM injection  Randomized, double-blind phase IIa trial –Primary endpoint: safety, tolerability of CAB LA IM injections –2 HIV seroconversions, none during CAB LA dosing period CAB LA 800 mg IM every 12 wks (n = 106) Saline Placebo IM every 12 wks (n = 21) Healthy adult men at low risk of HIV infection (N = 127) Oral PhaseInjection Phase CAB 30 mg PO QD Placebo PO QD Wk 4 Wk 41 Markowitz M, et al. CROI 2016. Abstract 106. 40-Wks of follow-up Slide credit: clinicaloptions.comclinicaloptions.com

12.  Peak CAB LA exposure higher and trough exposure lower than predicted because of more rapid absorption and release after injection –~ 70% of pts had C trough < 4 x protein-binding adjusted IC 90 ; every-8-wk dosing now under investigation Mean (SD) Plasma CAB Concentration (μg/mL) Time From First IM Dose (Wks) Markowitz M, et al. CROI 2016. Abstract 106. Reproduced with permission. Geometric mean C trough with 10 mg PO QD: 1.35 μg/mL (LATTE) 4 x Protein-binding adjusted IC 90 : 0.664 μg/mL Protein-binding adjusted IC 90 : 0.166 μg/mL 10 1 0.1 0.01 014812131824253036 Observed CAB 800 mg IM every 12 wks (ÉCLAIR; n = 94) Simulated CAB 800 mg IM every 12 wks (males) Slide credit: clinicaloptions.comclinicaloptions.com ÉCLAIR: Predicted vs Observed Cabotegravir LA Pharmacokinetics

13. ÉCLAIR: Injection Safety and Pain Outcomes  ISR events occurred in 93% of pts with IM CAB vs 57% with placebo  No discontinuations for AEs during inj. phase; however, 4 pts who withdrew consent noted inj. tolerability as reason  On 0 (none of time) to 6 (all of time) pain/discomfort scale assessed at Wk 30, 6% of pts in CAB arm reported pain/ discomfort all of the time –21% of pts in CAB arm reported being dissatisfied with study medication AEs Markowitz M, et al. CROI 2016. Abstract 106. Murray M, et al. CROI 2016. Abstract 471. Reproduced with permission. ISR Event CAB (n = 94)Placebo (n = 21) Events, % Mean Duration, Days Events, % Mean Duration, Days Pain 925.4272.0  Gr 1 4526  Gr 2 372  Gr 3 100 Pruritus 102.561.8 Swelling 83.80 Nodule/ bump 89.70 Warmth 73.20 Bruising 63.322.0 Induration 64.30 Slide credit: clinicaloptions.comclinicaloptions.com

14.  Pt satisfaction assessed by questionnaire at Wk 18 of IM treatment; asked pts to compare satisfaction of current IM vs past oral therapy [1]  In separate macaque study, CAB LA conferred 88% protection (21/24 animals) against IV exposure to SIVmac251; results may be relevant to humans who inject drugs [2] ÉCLAIR: Patient Satisfaction With IM Therapy vs Oral Phase Slide credit: clinicaloptions.comclinicaloptions.com 1. Markowitz M, et al. CROI 2016. Abstract 106. 2. Andrews CD, et al. CROI 2016. Abstract 105. Reproduced with permission. Pts (%) How satisfied are you with your current treatment? 100 80 60 40 20 0 Placebo (n = 21) CAB (n = 91) MoreNeutralLess 100 80 60 40 20 0 How satisfied would you be to continue with your present form of treatment? 62 23 71 29 74 81 15 24 5 Placebo (n = 21) CAB (n = 91) 15 11 19 0

15. HPTN-069/A5305: Maraviroc-Based PrEP for MSM  Randomized, double-blind phase II trial –Primary endpoints: safety (grade ≥ 3 AEs), tolerability (rate/time to discontinuation of study drug) Gulick R, et al. CROI 2016. Abstract 103. MVC 300 mg (n = 101) MVC 300 mg + FTC* (n = 106) HIV-uninfected men with condomless anal intercourse with ≥ 1 HIV+ or HIV unknown man in previous 90 days (N = 406) Wk 48 *Standard dosing. MVC 300 mg + TDF* (n = 99) FTC + TDF* (n = 100) Slide credit: clinicaloptions.comclinicaloptions.com

16. HPTN-069/A5305: Safety, Tolerability, and Efficacy  67 grade 3/4 AEs; rates similar across arms  9% discontinued study drug early –Rates of study drug discontinuation (P =.6) and time to permanent discontinuation (P =.6) similar across arms  5 new HIV infections occurred during study for annual incidence rate of 1.4% (95% CI: 0.8-2.3); all R5 tropic; no transmitted drug resistance Age (Yrs), Race of Newly Infected Pt Study Arm First HIV+ Test, Wk HIV-1 RNA, c/mL Plasma Drug Conc. at Seroconv. Visit (ng/mL)* 20, blackMVC + TDF4122,150MVC: 0 † TFV: 0 61, AsianMVC alone16981MVC: 145 21, mixed raceMVC alone24106,240MVC: 0 † 35, whiteMVC alone3213,626MVC: 6.7 36, blackMVC alone 48 52,191MVC: 0.7 Gulick R, et al. CROI 2016. Abstract 103. Reproduced with permission. *Anticipated predose steady-state MVC concentration: 32 ng/mL. † Undetectable plasma drug concentrations at every study visit. Slide credit: clinicaloptions.comclinicaloptions.com

17. Initial Antiretroviral Therapy

18. MK-1439-007: Doravirine + TDF/FTC vs EFV + TDF/FTC In Treatment-Naive Pts  Doravirine: investigational NNRTI with potent activity against common NNRTI resistance mutations, QD dosing, no PPI drug–drug interactions, improved CNS safety vs EFV in early studies  Part 2 of 2-part randomized, double-blind phase II study –Primary endpoint: HIV-1 RNA < 40 copies/mL at Wk 48 ART-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL, CD4+ cell count ≥ 100 cells/mm 3 (N = 132)* Wk 48 Doravirine 100 mg QD + TDF/FTC (n = 66) Efavirenz 600 mg QD + TDF/FTC (n = 66) Wk 96 *42 pts receiving doravirine 100 mg QD + TDF/FTC and 43 pts receiving efavirenz 600 mg QD + TDF/FTC in part 1 of this study were included in this analysis. Gatell JM, et al. CROI 2016. Abstract 470. Slide credit: clinicaloptions.comclinicaloptions.com

19. MK-1439-007: Primary Endpoint Gatell JM, et al. CROI 2016. Abstract 470. Reproduced with permission. 78.7 77.8 81.5 73.1 72.9 57.5 63.0 42.1 26.9 47.2 27.8 12.0 15.7 6.5 3.7 04812162024283236404448 100 80 60 40 20 0 Doravirine 100 mg Efavirenz 600 mg Wk 48 HIV-1 RNA < 40 c/mLn/N (%) Doravirine84/108 (77.8) Efavirenz85/108 (78.7) Difference (95% CI): -1.1 (-12.2 to 10.0) Treatment Wk HIV-1 RNA < 40 c/mL (NC = F), % (95% CI) Slide credit: clinicaloptions.comclinicaloptions.com

20. MK-1439-007: Clinical Adverse Events Gatell JM, et al. CROI 2016. Abstract 470. Reproduced with permission. Clinical AEs, %DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) Difference, DOR–EFV (95% CI) ≥ 1 AE87.088.9-1.9 (-10.9 to 7.1) Serious AEs6.58.3-1.9 (-9.5 to 5.6) Death00 D/c for AEs2.85.6-2.8 (-9.2 to 3.0) Drug-related AEs*31.556.5-25.0 (-37.3 to 11.8)  Diarrhea0.96.5  Nausea7.45.6  Dizziness6.525.9  Headache2.85.6  Abnormal dreams5.614.8  Insomnia6.52.8  Nightmares5.68.3  Sleep disorder4.66.5 *Specific AEs occurring in ≥ 5% of pts included. Slide credit: clinicaloptions.comclinicaloptions.com

21. Switch and Maintenance Strategies for Virologically Suppressed Patients

22. GS-1089: Switch From Suppressive TDF- to TAF-Containing ART: Wk 48 Efficacy  Randomized, double-blind, active-controlled phase III trial –Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 by ITT FDA snapshot; noninferiority margin 10% *FTC/TAF dosing: 200/10 mg with boosted PIs; 200/25 mg with unboosted third drug. HIV-1 RNA < 50 c/mL at Wk 48, % Gallant JE, et al. CROI 2016. Abstract 29. Treatment difference: 1.3% (95% CI: -2.5% to 5.1%) Slide credit: clinicaloptions.comclinicaloptions.com Switch FTC/TDF to FTC/TAF* Continue third ARV (n = 333) Continue FTC/TDF Continue third ARV (n = 330) HIV-infected pts with HIV-1 RNA < 50 c/mL, eGFR ≥ 50 mL/min while receiving FTC/TDF + third ARV (N = 663) Wk 48 Wk 96 94.3 93.0

23. GS-1089: Renal Outcomes With Switch From TDF- to TAF-Containing ART  No proximal renal tubulopathy or Fanconi syndrome in either arm Slide credit: clinicaloptions.comclinicaloptions.com Median eGFR Change (mL/min) Wk 8.4 2.8 P <.001 TAF 40 20 0 -20 -40 Median % Change at Wk 48 ProteinAlbuminRBPβ2-M Urine Protein-to-Creatinine Ratio 7.7 -14.6 -7.7 -16.3 -39.6 12.3 18.2 22.0 TDF P <.001 Gallant JE, et al. CROI 2016. Abstract 29. Reproduced with permission. 20 10 0 -10 012243648

24. GS-1089: BMD Changes With Switch From TDF- to TAF-Containing ART Slide credit: clinicaloptions.comclinicaloptions.com Gallant JE, et al. CROI 2016. Abstract 29. Reproduced with permission. Spine 4 2 0 Mean % change in BMD (95% CI) 1.5 -0.2 P <.001 BL2448 Wks FTC/TAF, n FTC/TDF, n 321 320 310 300 306 Hip 4 2 0 1.1 -0.2 BL2448 Wks 321 317 309 305 300 303 P <.001 ≥ 3% BMD Increase at Wk 48, %FTC/TAFFTC/TDFP Value Spine3014<.001 Hip179.003

25. LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART  Multicenter, open-label phase IIb study –Primary endpoints: HIV-1 RNA < 50 c/mL by FDA snapshot, PDVF, and safety at maintenance Wk 32 Slide credit: clinicaloptions.comclinicaloptions.com Margolis DA, et al. CROI 2016. Abstract 31LB. CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115) *Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. 6 pts discontinued for AEs or death in induction analysis. ART-naive HIV- infected pts with CD4+ cell count > 200 cells/mm 3 (N = 309) CAB 30 mg PO + ABC/3TC PO QD (n = 56) CAB 30 mg PO QD + ABC/3TC Wk 32 primary analysis; dose selection Wk 20 Induction Phase*Maintenance Phase Wk 1Wk 96 Wk 16: RPV PO added

26. LATTE-2: Maintenance Wk 32 Virologic Efficacy (ITT-Maintenance Exposed)  Virologic efficacy of Q4W and Q8W IM regimens similar to oral regimen  No INSTI, NNRTI, or NRTI resistance mutations detected Slide credit: clinicaloptions.comclinicaloptions.com Margolis DA, et al. CROI 2016. Abstract 31LB. Reproduced with permission. 95 94 91 4 < 1 4 5 5 Virologic Success Virologic Non- response No Virologic Data HIV-1 RNA <50 c/mL (%) 100 80 60 40 20 0 IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56) Treatment Differences (95% CI) Q8W -4.8 3.7 12.2 IMOral -12-10-8-6-4-2024681012 Q4W -5.8 2.8 11.5 -12-10-8-6-4-2024681012

27. LATTE-2: Safety Through Maintenance Wk 32  Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%) –ISR events/injection: 0.53 –99% of ISRs grade 1/2; none grade 4 –Proportion of pts reporting ISRs decreased with time from 86% on Day 1 to 33% at Wk 32; 1% of pts withdrew for ISRs Slide credit: clinicaloptions.comclinicaloptions.com Margolis DA, et al. CROI 2016. Abstract 31LB. AEs, %Pooled CAB + RPV IM Arms (n = 230) Oral CAB + ABC/3TC (n = 56) Drug-related grade 3/4 AEs (excluding ISRs) 30 Serious AEs 65 AEs leading to withdrawal 32

28. LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction Slide credit: clinicaloptions.comclinicaloptions.com Margolis DA, et al. CROI 2016. Abstract 31LB. Reproduced with permission. Pts (%) How satisfied are you with your current treatment? 100 80 60 40 20 0 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) MoreNeutralLess 100 80 60 40 20 0 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) MoreNeutralLess How satisfied would you be to continue with your present form of treatment? 979671 29 3 1 3 98 71 29 2 1 1

29. Second-line Antiretroviral Therapy

30. ACTG 5273: Second-line LPV/RTV + NRTIs vs LPV/RTV + RAL in African Settings HIV-infected pts with HIV-1 RNA > 1000 copies/mL after initial ART with NNRTI + NRTIs (N = 512) Wk 48: primary endpoint Lopinavir/Ritonavir + Raltegravir (n = 258) Lopinavir/Ritonavir + Best Available NRTIs* (n = 254) Wk 96 † *NRTIs selected according to algorithm, including substitution of zidovudine for tenofovir DF and vice versa. † Shortened to 52 wks after last enrollment. La Rosa AM, et al. CROI 2016. Abstract 30.  Open-label, noninferiority phase III study –Primary endpoint: time to VF (confirmed HIV-1 RNA > 400 c/mL at or after 24 wks) Slide credit: clinicaloptions.comclinicaloptions.com

31. ACTG 5273: Virologic Failure and Toxicity  No differences in number of AIDS events, serious non-AIDS events, or deaths between arms  Difference in VF through Wk 48: –RAL – NRTIs: -3.4% (95% CI: -8.4% to 2.5%) –Upper bound of CI < 10%: RAL noninferior –Upper bound of CI > 0: RAL not superior  Cumulative probability of grade ≥ 3 toxicity event higher with LPV/RTV + NRTIs vs LPV/RTV + RAL –Stratified log-rank P =.040  Greater increases in total, LDL-, and non-HDL cholesterol and triglycerides with RAL vs NRTIs La Rosa AM, et al. CROI 2016. Abstract 30. Slide credit: clinicaloptions.comclinicaloptions.com

32. ACTG 5273: Impact of Baseline Resistance on Risk of Virologic Failure  No differences between arms, or after adjustment for baseline HIV-1 RNA, Wk 4 adherence, previous TDF use, country [1]  ACTG 5273 overall results consistent with EARNEST, SECOND-LINE trials [2,3] 1. La Rosa AM, et al. CROI 2016. Abstract 30. 2. Paton NI, et al. N Engl J Med. 2014;371:234-247. 3. Amin J, et al. PLoS One. 2015;10:e0118228. Baseline NRTI ResistanceHR for VF in Both Arms (95% CI) P Value K65R, ≥ 3 TAMs, Q151M or 69 ins/del  Yes vs no (ref) 0.49 (0.31-0.76).001 IAS NRTI mutations  ≥ 3 vs < 3 (ref) 0.45 (0.30-0.70)<.001 K65R and/or M184V/I  No K65R but M184V/I vs no M184V/1 (ref)  K65R and M184V/I vs no M184V/1 (ref) 0.41 (0.25-0.67) 0.19 (0.08-0.44) <.001 Slide credit: clinicaloptions.comclinicaloptions.com

33. Antiretroviral Therapy During Pregnancy

34. IMPAACT P1026s: DTG in Pregnancy  Ongoing, nonrandomized, open-label phase IV study in HIV+ pregnant women [1]  DTG 50 mg QD: PK assessed during 2nd, 3rd trimester, 3-12 wks postpartum, and in infants  N = 21 women –HIV-1 RNA ≤ 50 c/mL in 2nd and 3rd trimester: 100% –Median gestational age at birth: 38.9 wks –9/18 infants HIV negative; HIV status pending in 9/18  DTG trough and AUC exposure lower in 2nd and 3rd trimester vs postpartum  Antepartum DTG exposure similar to nonpregnant adults  DTG elimination half-life > 2-fold higher in infants vs nonpregnant adults  Congenital anomalies in 4 infants  Antiretroviral Pregnancy Registry : 0/10 (1st trimester) and 1/18 (2nd or 3rd trimester) birth defects with DTG exposure [2] 1. Mulligan N, et al. CROI 2016. Abstract 438. 2. APR. http://www.apregistry.com. Slide credit: clinicaloptions.comclinicaloptions.com

35. P1084s: Effect of TDF During Pregnancy on Newborn Bone Mineral Content  Newborn BMC compared between mothers randomized to one of the following in pregnancy: –ZDV (+ sdNVP + TDF/FTC tail) –LPV/RTV + ZDV/3TC –LPV/RTV + TDF/FTC  Infant DXA scans at age 0-21 days  Newborn mean lumbar spine BMC similar between Tx arms  Newborn mean whole body BMC significantly lower in LPV/RTV arms vs ZDV (+ sdNVP + TDF/FTC tail); no significant difference ± TDF Siberry GK, et al. CROI 2016. Abstract 36. Whole Body BMC Comparison UnadjustedAdjusted* Mean Difference, gP ValueMean Difference, gP Value LPV/RTV + ZDV/3TC vs LPV/RTV + TDF/FTC +1.76.41+1.22.50 ZDV (+ sdNVP + TDF/FTC tail) vs LPV/RTV + TDF/FTC +9.73<.001 +8.69<.001 ZDV (+ sdNVP + TDF/FTC tail) vs LPV/RTV + ZDV/3TC +7.97<.001+5.82.002 *Adjusted for country, maternal age at entry and height, and infant age and length at time of DXA. Slide credit: clinicaloptions.comclinicaloptions.com

36. Treatment Complications and Comorbidities

37. EuroSIDA: Impact of TDF Exposure on Risk of Fractures in HIV-Infected Pts  Prospective analysis of 11,820 HIV-infected pts  Followed from baseline (Jan 2004) to last visit or death to assess for fractures, femoral osteonecrosis Borges AH, et al. CROI 2016. Abstract 46. Reproduced with permission. TDF Exposure Any Fracture IRR (95% CI) Osteoporotic Fracture* IRR (95% CI) UnivariateMultivariate † Ever used vs never used 1.71 ‡ (1.42-2.06)1.40 ‡ (1.15-1.70)1.10 (0.76-1.58) On TDF vs not on TDF 1.38 ‡ (1.16-1.64)1.25 ‡ (1.15-1.70)1.12 (0.79-1.60) Cumulative TDF exposure/5 yrs 1.28 ‡ (1.13-1.50)1.08 (0.94-1.25)0.99 (0.69-1.43) *Fracture of the spine, arm, wrist, or hip. † Adjusted for demographics, HIV-specific variables, and comorbidities. ‡ P <.05 Slide credit: clinicaloptions.comclinicaloptions.com

38. EuroSIDA: Association Between Use of Specific ARVs and Risk of Osteonecrosis Borges AH, et al. CROI 2016. Abstract 46. Reproduced with permission. *Race, previouis femoral necrosis at baseline, fracture, nadir CD4+ cell count, age, AIDS and non-AIDS- defining malignancy, nonmalignant AIDS event. TDFLPV/ RTV SQVIDVddITDFLPV/ RTV SQVIDVddI Ever Used ARV 0.5 5.0 1.99 1.75 1.97 1.77 1.70 1.42 1.39 1.55 1.39 1.43.25.17.20.27.051.031.015.027.013P Value: Adjusted* IRR for Osteonecrosis (95% CI) Each ARV included in separate model and adjusted for all other variables* Each ARV mutually adjusted for use of the other ARVs and adjusted for all other variables* Slide credit: clinicaloptions.comclinicaloptions.com

39. GS 104/111: Renal Safety of TAF vs TDF in Patients at High Risk of Kidney Disease  GS 104 and 111: randomized, double blind 144-Wk studies of E/C/F/TAF vs E/C/F/TDF in 1744 ART-naive pts with eGFR ≥ 50 mL/min [1]  Post hoc analysis of renal outcomes by baseline CKD risk category and by D:A:D risk score [2] –High CKD risk: ≥ 2 renal risk factors (female sex, age ≥ 50 yrs, black race, NSAID use, CD4+ < 200 cells/mm 3, history of dyslipidemia, hypertension, diabetes, and clinical or subclinical renal events) –Low CKD risk: ≤ 1 renal risk factor  Improved renal outcomes with TAF vs TDF with high or low CKD risk –Incident CKD through 2 yrs: TAF 0.1% vs TDF 1.6% –Fewer discontinuations for renal AEs, changes in eGFR CG, quantitative proteinuria with TAF in all CKD risk groups 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Wohl D, et al. CROI 2016. Abstract 681. Slide credit: clinicaloptions.comclinicaloptions.com

40. Comparison of CVD Risk Scores in HIV- Infected Pts  Compared expected and observed MI event rates using 4 risk scores in 10,832 HIV-infected pts with 229 incident MI events in CNICS –3 general population CVD risk scores (Framingham, ATP3, 2013 ACC/AHA ASCVD) plus HIV-specific D:A:D score in CNICS pts  Variations across models anticipated given differences in outcome  ART use (ie, D:A:D score) did not improve discrimination vs ASCVD  Discrimination greater with ASCVD vs other models for all outcomes –Harrell’s C for MI with ASCVD –Type 1 MI: 0.77 (CI: 0.73-0.81) –Type 2 MI: 0.72 (CI: 0.67-0.78) –All MI: 0.74 (CI: 0.71-0.77) Crane HM, et al. CROI 2016. Abstract 42. Slide credit: clinicaloptions.comclinicaloptions.com

41. Trends in HIV Outcomes

42. HIV positive Dots: Expected yrs of life remaining at age 20 Kaiser Permanente: Life Expectancy in HIV-Infected vs Uninfected Persons  Analysis of life expectancy in 24,768 HIV-infected and 257,600 HIV-uninfected adult pts in Kaiser Permanente California 1996-2011; 2 groups matched for age, sex, medical center, yr Marcus JL, et al. CROI 2016. Abstract 54. Reproduced with permission. HIV negative Lines: Deaths per 100,000 PYs 8000 6000 4000 2000 0 80 60 40 20 0 439 19 63 7077 65 53 1054 381 P <.001 P =.062 13-Yr Gap 1996- 1997 1998- 1999 2000- 2001 2002- 2003 2004- 2005 200620072008200920102011 Slide credit: clinicaloptions.comclinicaloptions.com

43. KP: Factors Contributing to Reduced Life Expectancy With HIV (2008-11) Marcus JL, et al. CROI 2016. Abstract 54. Reproduced with permission. Factor Expected Yrs of Life Remaining at Age 20 Yrs HIV Infected and Began ART With CD4+ ≥ 500 cells/mm 3 HIV Uninfected Difference (95% CI) Overall54.562.37.9 (5.1-10.6)  No HBV or HCV55.462.67.2 (4.4-10.0)  No drug or alcohol abuse 57.263.86.6 (3.9-9.3)  No smoking58.964.35.4 (2.2-8.7)  None of the above 59.265.05.7 (2.4-9.0) Slide credit: clinicaloptions.comclinicaloptions.com

44. Bradley H, et al. CROI 2016. Abstract 53. Reproduced with permission. *HIV-1 RNA < 200 c/mL at last test. † HIV-1 RNA < 200 c/mL at all tests from previous 12 mos. 100 80 60 40 20 0 Pts (%) 20092010201120122013 Yr β trend =.01 β trend =.02 β trend =.03 58 60 62 66 68 72 74 76 77 80 89 90 92 93 94 ART prescriptionViral suppression*Sustained viral suppression † Slide credit: clinicaloptions.comclinicaloptions.com Increasing Rates of Viral Suppression in United States From 2009-2013  Medical Monitoring Project 2009-2013: surveillance data on ART prescription and viral suppression in adults

45. Ribaudo HJ, et al. CROI 2016. Abstract 476. Reproduced with permission. 0.5 0.4 0.3 0.2 0.1 0 Cumulative VF Probability Wks Since Study Entry 019224486480 128 16096 Women Men Wk 96 Unadjusted HR Women vs Men: 1.4 (95% CI: 1.1-1.9; P =.026) Slide credit: clinicaloptions.comclinicaloptions.com 0.5 0.4 0.3 0.2 0.1 0 Wks Since Study Entry 01922448648011212814416017696 Black Hispanic White Wk 96 Unadjusted HR Black vs White: 2.8 (95% CI: 2.0-3.8; P <.001) Wk 96 Unadjusted HR Hispanic vs White: 2.0 (95% CI: 1.4-2.8; P =.001) 112144176 ACTG A5257: Sex and Racial Disparities in Virologic Outcomes With ART  Randomized phase III comparison of ATV/RTV vs RAL vs DRV/RTV (each with FTC + TDF) in ART-naive pts  Current analysis compared virologic outcomes in A5257 by sex and race/ethnicity

46. ACTG A5257: Multivariable Analysis of Risk Factors Associated With VF  Race/ethnicity adjustment eliminated excess VF risk for women (P =.20)  Sociodemographic factor adjustment eliminated excess VF risk for Latinos (aHR: 1.16; 95% CI: 0.74-1.84), but not for black pts (aHR: 1.68; 95% CI: 1.14-2.46)  Additional factors associated with increased VF risk: younger age, recent nonadherence, underweight, high baseline HIV-1 RNA, low income, less education, and history of IV drug use Ribaudo HJ, et al. CROI 2016. Abstract 476. Slide credit: clinicaloptions.comclinicaloptions.com

47. Go Online for More CCO Coverage of CROI 2016! Capsule Summaries of the most clinically relevant new data On-demand audio of post-CROI Webinar with expert faculty commentary on the clinical impact of key studies clinicaloptions.com/HIV/Retroviruses 2016