1. Joel Gallant, MD, MPH Johns Hopkins University School of Medicine ART Update

2. When to Start

3. When to Start: DHHS Guidelines 02/12/2013 US DHHS Guidelines, February 2013. ART recommended for all HIV+ individuals to reduce risk of disease progression. Strength and evidence for recommendation vary by pre- treatment CD4 count: CD4 ≤ 350 CD4 350-500 CD4 >500 AI AII BIII 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 AIII

4. When to Start IAS-USA Guidelines, July 2012 US DHHS Guidelines, January 2011. Clinical Condition and/or CD4 Count Recommendations CD4 ≤500 CD4 >500 AIa BIII Pregnancy HIV-associated nephropathy HBV coinfection HCV coinfection Age >60 Acute phase of primary infection AIa AIIa CIII BIIa BIII ART recommended and should be offered regardless of CD4 count. Strength of recommendation varies based on CD4 count: Thompson MA, et al. JAMA 2012;308:387-402

5. Why abandon CD4 thresholds? Observational data showing improved survival and/or lack of harm Association between copy-year viremia and morbidity and mortality Presumed benefit of reducing inflammation and immune activation Minimal incremental difference between treating everyone vs. treating a CD4 of 500 Prevention

6. Frequent CD4 Count Monitoring Not Necessary for Patients With CD4 > 300  Retrospective review of VA lab database of > 25,000 paired VL and CD4 counts from 1821 unique pts (1998 -2011)  Eligible pts had “sequences”: consecutive VL/CD4 pairs with –VL < 200 –CD4 count > 200 –%CD4 >14 –< 390 days between CD4 counts  Analysis of pts with sequences (n = 846) who experienced CD4 “dips” < 200 during periods of virologic suppression (n = 61)  Virologically suppressed pts with CD4 > 300 extremely unlikely to have CD4 count dip < 200 Gale H, et al. AIDS 2012. Abstract WEPDB0101. Probability Viral Suppression, Yrs 0123456 0.50 0.60 0.70 0.80 0.90 1.00 ≥ 350 300-349 250-299 200-249 Probability of Maintaining CD4 >200 During Viral Suppression DHHS Guidelines: “In clinically stable patients with suppressed viral load, CD4 count can be monitored every 6–12 months”

7. The Initial Regimen

8. DHHS Guidelines, Febuary 2013: What to Start Preferred Regimens NNRTI based  EFV/TDF/FTC Boosted PI based  ATV/r + TDF/FTC  DRV/r + TDF/FTC INSTI based  RAL + TDF/FTC Alternative Regimens NNRTI based  EFV + ABC/3TC  RPV/TDF/FTC or RPV + ABC/3TC (VL <100,000) Boosted PI based  ATV/r + ABC/3TC  DRV/r + ABC/3TC  FPV/r + (ABC/3TC or TDF/FTC)  LPV/r + (ABC/3TC or TDF/FTC) INSTI based  RAL + ABC/3TC  EVG/COBI/FTC/TDF(eGFR >70) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. February 2013

9. IAS-USA Guidelines, July 2012: What to Start Recommended Regimens NNRTI based  EFV/TDF/FTC or EFV + ABC/3TC*  Boosted PI based  ATV/r + (TDF/FTC or ABC/3TC*  )  DRV/r + TDF/FTC INSTI based  RAL + TDF/FTC Alternative Regimens ‡ NNRTI based  NVP + (TDF/FTC or ABC/3TC*  )  RPV/TDF/FTC or RPV + ABC/3TC*  Boosted PI based  DRV/r + ABC/3TC  LPV/r  + (TDF/FTC or ABC/3TC*  ) INSTI based  RAL + ABC/3TC*   EVG/COBI/TDF/FTC Thompson MA, et al. JAMA 2012;308:387-402 *HLA-B*5701 screening recommended before ABC administration to reduce risk of HSR..  Consider avoiding use of ABC or LPV/r for pts with or at high risk of CV disease. ‡ ZDV/3TC is alternative NRTI component of NNRTI-, PI/r-, and RAL-based regimens, but toxicity profile of ZDV reduces its utility.

10. NNRTIs

11. NNRTIAbb.Brand Name(s)Comments NevirapineNVPViramune, Viramune XRWomen: CD4<250 Men: CD4 <400 DelavirdineDLVRescriptorRarely used EfavirenzEFVSustiva (Atripla)Preferred NNRTI for initial therapy EtravirineETRIntelenceART-experienced patients RilpivirineRPVEdurant (Complera)VL <100,000; no PPIs/H2 blockers; with meal NNRTIs

12. ECHO/THRIVE: Viral Load <50, 96 Week ITT-TLOVR Data RPV Cohen C, et al. J Acquir Immune Defic Syndr. 2012

13. ECHO/THRIVE: RPV vs EFV: 96 Week Results by Baseline VL ≤100K >100K 75 8480 4.0 (–1.7, 9.7) -5.2 (-12, 1.5) 70 RPV Responders Discontinued due to other reasons † VF eff Discontinued due to AE/death EFV Non responders RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR (138K mutation) EFV: More adverse effects (rash, CNS side effects), greater increase in lipids RPV: More virologic failures and NNRTI/NRTI resistance; cross-resistance with ETR (138K mutation) EFV: More adverse effects (rash, CNS side effects), greater increase in lipids Cohen C, et al. J Acquir Immune Defic Syndr. 2012

14. 95% CI for Difference Proportion of Subjects, % 4.1-1.19.2 -12012 Favors EFV/FTC/TDF Favors RPV/FTC/TDF % % RPV/FTC/TDF non-inferior to EFV/FTC/TDF STaR: RPV/TDF/FTC vs. EFV/TDF/FTC Week 48FDA Snapshot Analysis – ITT Population RPV/FTC/TDF EFV/FTC/TDF (VL<50 c/mL) CD4 change : RPV/FTC/TDF +200 vs EFV/FTC/TDF +191 (p=0.34) 338/ 394 320/ 392 32/39422/39224/39450/392 p=0.12 Cohen C, et al. 11th Int’l Conf on Drug Therapy in HIV Infection, Glasgow, 2012

15. STaR: RPV/TDF/FTC vs. EFV/TDF/F Virologic Suppression by Baseline Viral Load 204/ 250 81/ 98 96/ 117 26/ 36 20/ 25 * Post hoc analyses; analyses for non-inferiority only pre-specified for ≤100,000 c/mL and >100,000 c/mL * 231/ 260 Baseline VL c/mL * 2% 1% 8%0% 19% 4% Cohen C, et al. 11th Int’l Conf on Drug Therapy in HIV Infection, Glasgow, 2012

16. SPIRIT: Switch to RPV/TDF/FTC From Boosted-PI Regimens in Suppressed Pts Switch to RPV/TDF/FTC noninferior to maintaining boosted-PI regimen at Wk 24 –93.7% vs 89.9% with VL < 50 –Noninferior regardless of pretreatment VL stratum 17/17 with baseline K103N maintained suppression after switch Sig. reductions in TC, LDL, TG, HDL, TC:HDL ratio (P <.001) and in 10-yr Framingham score (P =.001) at Wk 24 with switch VL< 50 at Wk 24 RPV/TDF/FTCBoosted PI 40 0 100 20 80 89.2 95.0 60 83/ 93 152/ 160 n = ≥ 100K Pts With VL < 50 c/mL (%) 92.3 95.5 128/ 134 48/ 52 < 100K 89.9 93.7 Overall Δ 3.8% (-1.6 to 9.1) Δ 3.2% (-4.8 to 11.3) Δ 5.9% (-1.4 to 12.9) *Excludes 23 RPV and 14 boosted PI pts lacking baseline VL while ARV naive. Palella F, et al. AIDS 2012. Abstract TUAB0104. 317159 Baseline VL (When Naive)*

17. Switching From TDF/FTC/EFV to TDF/FTC/RPV in Suppressed Pts Single-arm study of 50 pts virologically suppressed on TDF/FTC/EFV as first regimen for ≥ 3 mos –No known resistance mutations to study meds –Desiring to switch to TDF/FTC/RPV for intolerance of regimen 100% Mills A, et al. ICAAC 2011. Abstract H2-794c.

18. Integrase Inhibitors

19. INSTIAbb.Brand Name(s)Comments RaltegravirRALIsentressTwice daily ElvitegravirEVGStribild (EVG/COBI/TDF/FTC) Once-daily boosted Coformulation only DolutegravirDVG?Once-daily unboosted; coming soon Integrase Inhibitors

20. STARTMRK: Final 5-Yr Phase III Results of Efavirenz vs Raltegravir in Naive Pts  Double-blind phase III trial of EFV vs RAL, with TDF/FTC, in ART-naïve pts  RAL noninferior at Wk 48 1 o endpoint  RAL superior to EFV at 192-240 wks by VL < 50 (ITT, NC = F analysis)  CD4 gain: +374 (RAL) vs +312 (EFV)  Consistent virologic and immunologic effects by subgroup (e.g., baseline CD4/VL, age, sex, race, etc.)  Low levels of resistance among patients with VF and VL > 400 in both arms –RAL, n = 7; EFV, n = 12  Fewer drug-related AEs in RAL arm  Smaller increases in TC, HDL-C, LDL- C, and TG levels with RAL vs EFV 61 71 240 279 RAL EFV Pts With VL < 50 c/mL (%) Wks 100 80 60 40 20 0 024487296120168 86 82 81 79 75 69 192 76 67 Wk 240 ∆ = +9.5 (95% CI, 1.7-17.3) Noninferiority P <.001 21614412 281279280281 277281 277280278 282 281282 281282 281282 Pts, n Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013

21. GS 102: EVG/COBI/TDF/FTC vs. TDF/FTC/EFV: VL <50 Virologic SuccessVirologic Nonsuppression No data at W48 (or 96) Percentage of subjects (%) “Quad” (n=348) EFV/TDF/FTC (n=352) 95% CI for Difference Favors EFV/TDF/FTCFavors Quad W48 0 -12% -1.6%8.8% 3.6% W96 -2.9%8.3% 2.7% 12% Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

22. GS 102: Common Neuropsychiatric AEs Abnormal Dreams Dizziness Patients with AE (%) Weeks “Quad” (n=348) EFV/TDF/FTC (n=352) Incidence (bar) and Prevalence (line) Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

23. GS 102: Changes in serum creatinine STB (n=)348328320305298 ATR (n=)352317307302295 0.14 0.13 0.01 Discontinuation due to renal A/Es EVG/COBI/TDF/FTC 1.4% 2.0% EFV/TDF/FTC 0% 0% Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

24. GS 102: Drug Resistance Through Week 96 “Quad” (n=348) EFV/TDF/FTC (n=352) BL-Week 48BL-Week 96BL-Week 48BL-Week 96 Subjects Analyzed for Resistance*, n (%) 14 (4%)17 (5%) 23 (7%) Subjects with Resistance to ARV Regimen, n (%) 8 (2%)10 (3%)8 (2%)10 (3%) Any Primary INSTI-R, n79-- Any Primary NNRTI-R, n--810 Any Primary NRTI-R, n81023 * Subjects who experienced either suboptimal virologic response (VL ≥50 c/mL and 1 log 10 increase from nadir), or had VL ≥400 c/mL at Week 48, Week 96, or their last visit (at or after Week 8). Zolopa A, et al. J Acquir Immune Defic Syndr 2013.

25. Virologic SuccessVirologic Non suppression No data at W48 (or 96) Percentage of subjects (%) EVG/COBI/FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) 95% CI for Difference Favors ATV/r + FTC/TDF Favors EVG/COBI/FTC/TDF 0 -12% 12% 7.5 W48 -2.1 2.7 W96 -4.5 6.7 1.1 11 Figure 1: Efficacy (Snapshot Analysis) through Week 48 (Primary) and Week 96 (Secondary) GS 103: EVG/COBI/TDF/FTC vs. TDF/FTC + ATV/r: VL <50 Rockstroh JK, et al. J Acquir Immune Defic Syndr 2013.

26. GS 103: Changes in Serum Creatinine Median change W48: 0.12 mg/dL vs. 0.08 mg/dL (Quad vs. ATV/r + FTC/TDF group, p<0.001) BL248121624324048 0.28 0.24 0.20 0.16 0.12 0.08 0.04 0.0 -0.04 -0.08 Change from Baseline in Serum Creatinine (mg/dL) Week QUAD (n=): 353346344344340337334325324323 ATV/r +FTC/TDF (n=):355344342339335332329323316314 DeJesus E, et al. Lancet 2012;379:2429-38

27. GS 103: Drug resistance through week 48 “Quad” (n=353) ATV/r + FTC/TDF (n=355) Subjects Analyzed for Resistance a, n (%)12 (3)8 (2) Subjects with Resistance to ARV Regimen, n (%)5 (1)0 Any Primary Integrase-R, n4- E92Q1- T66I1- Q148R2- N155H2- Any Primary PI-R, n-0 Any Primary NRTI-R, n40 M184V/I4 K65R1 DeJesus E, et al. Lancet 2012;379:2429-38

28. SPRING-2: Dolutegravir Noninferior to Raltegravir at 48 Wks CD4 gain of +230 from BL in both arms No significant differences by baseline VL or NRTI backbone  Per protocol response: 90% (DTG) vs 88% (RAL) by snapshot analysis Δ 1.6% (95% CI: -2.7% to 5.9%) 88% 85% 100 80 60 40 20 0 BL48121624324048 Wk Pts With VL < 50 c/mL (%) DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Δ 2.5% (95% CI: -2.2% to 7.1%) Raffi F, et al. IAC 2012. Abstract THLBB04.

29. SPRING-2: Safety and Resistance Less confirmed virologic failure at or after Wk 24 with DTG vs RAL (5% vs 7%) 1. Raffi F, et al. IAC 2012. Abstract THLBB04. 2. Koteff J, et al. ICAAC 2011. Abstract A1-1728.  DTG had favorable safety profile, comparable to RAL –Few AEs necessitating discontinuation (2% in each arm) –Greater increase in creatinine with DTG vs RAL (+0.139 vs +0.053 mg/dL) –DTG increases serum creatinine by inhibiting renal creatinine secretion but does not affect actual GFR [2] –No premature discontinuation for renal events PatientsDTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Subjects with virologic failure, n2028 Resistance, n/N  INSTI resistance mutations  NRTI resistance mutations 0/8 0/12 1/18 4/19

30. SINGLE: Dolutegravir + ABC/3TC vs. EFV/TDF/FTC Week EFV/TDF/FTC QD DTG 50 mg + ABC/3TC QD BL248121624324048 0 10 20 30 40 50 60 70 80 90 100 Proportion (%) with <50 c/mL DTG+ABC/3TC: 88% EFV/TDF/FTC: 81% WK 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); p=0.003 ●DTG +ABC/3TC QD superior to EFV/TDF/FTC at Wk 48 (1 o endpoint) ●Subjects receiving DTG +ABC/3TC achieved faster suppression than EFV/TDF/FTC, med. time to FL <50 c/mL of 28 vs 84 days, P<0.0001 Walmsley S, et al. 52 nd ICAAC. 9-12 Sept 2012. Abstract H-556b.

31. Outcome (snapshot) at Week 48 DTG 50 mg +ABC/3TC n=411 n (%) EFV/TDF/FTC (N=419) n (%) Virologic success364 (88)338 (81) Virologic nonresponse21 (5)26 (6) Data in window not <50 c/mL6 (1)5 (1) Discontinued for lack of efficacy7(2)9 (2) Discontinued for other reason while not <50 c/mL8 (2)12 (3) No virologic data at Week 4829 (7)55 (13) Discontinued because of AE or death*9 (2)40 (10) Discontinued for other reasons20 (5)14 (3) Missing data during window but on study01 (<1) SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC: Disposition *Deaths: n=2, both on EFV/TDF/FTC: n=1 primary cause of death (sepsis) judged unrelated to study drug but complicated by renal failure judged possibly related to EFV/TDF/FTC; n=1 not related to EFV/TDF/FTC (pneumonia). Walmsley S, et al. 52 nd ICAAC. 9-12 Sept 2012. Abstract H-556b.

32. DTG 50mg +ABC/3TC (N=414) EFV/TDF/FTC (N=419) Subjects with PDVF18 (4%)17 (4%) PDVF genotypic population119 PDVF Genotypic (RT Results at Baseline and PDVF)99 NRTI tmt-emergent major mutations01(K65R) NNRTI tmt-emergent major mutations04 (K101E, K103N, G190A)* PDVF Genotypic (IN Results at Baseline and PDVF)77 INI-r tmt-emergent major substitution0** 0 * n=1 with K101E, n=1 with K103N, n=1 with G190A and n=1 with K103N+G190A **E157Q/P polymorphism detected with no significant change in IN phenotypic susceptibility SINGLE: DTG + ABC/3TC vs. EFV/TDF/FTC: Resistance Walmsley S, et al. 52 nd ICAAC. 9-12 Sept 2012. Abstract H-556b.

33. PIs

34. PIAbb.Brand Name(s)Comments SaquinavirSQVInviraseRarely used IndinavirIDVCrixivanRarely used RitonavirRTVNorvirUsed only as booster NelfinavirNFVViraceptRarely used Lopinavir/RTVLPV/rKaletraOnly coformulated PI; Once or twice daily Higher RTV dose than others FosamprenavirFPVLexivaInfrequently used AtazanavirATVReyatazOnce-daily boosted; Unboosted OK without TDF Jaundice; caution with PPIs TipranavirTPVAptivusRarely used; ART-experienced with TPV susceptibility and DRV resistance DarunavirDRVPrezistaOnce-daily in most cases; Twice daily if DRV mutations PIs

35. GS 114: Cobicistat-Boosted vs RTV- Boosted ATV in ART-Naïve Patients CD4 count gain: +213 with ATV/COBI vs +219 with ATV/r Among 24 pts with suboptimal virologic response and genotype: no primary PI or TDF resistance; M184V/I in 2 pts in COBI arm, 0 in RTV arm VL < 50 at Wk 48 (Snapshot Analysis) Gallant J, et al. J Infect Dis 2013. ATV/COBIATV/r 40 0 100 20 80 87 85 60 348344n = Baseline VL ≤ 100K Baseline VL > 100K Overall Patients (%) 88 84 86 179/ 212 181/ 205 114/ 132 123/ 143 Δ-2.2% (-7.4 to 3.0) P = NS Baseline CD4+ ≤ 350 Baseline CD4+ > 350 90 85 81 156/ 174 164/ 183 137/ 170 140/ 165 P = NS

36. COBI  serum creatinine and  eGFR by inhibiting renal creatinine secretion [1] COBI does not affect actual GFR [2] 6 pts in COBI arm and 5 in RTV arm D/C’d therapy due to renal abnormalities [3] Higher proportion with hyperbilirubinemia with COBI but discontinuations similar by arm 5 of 6 in COBI arm vs 2 of 5 in RTV arm with proximal tubulopathy discontinued therapy ATV/COBI vs ATV/r: Changes in Serum Creatinine and eGFR mg/dL Change in Serum Creatinine, Median (IQR) 1. Lepist EI, et al. ICAAC 2011. Abstract A1-1724. 2. German P, et al. J Acquir Immune Defic Syndr. 2012;[Epub ahead of print]. 3. Gallant J, et al. J Infect Dis 2013. ATV/COBI ATV/r 0.4 0.3 0.2 0.1 0.0 BL81624324048 Wk mL/min Change in eGFR, Median (IQR) 0 -10 -20 -30 -40 BL81624324048 Wk ATV/COBI ATV/r

37. PI News Coming soon? –DRV/COBI and ATV/COBI coformulations Coming later? –DRV/COBI/FTC/TAF (“D/C/F/TAF”) coformulation Awaiting results: –ACTG ARENT: DRV/r vs. ATV/r vs. RAL comparison

38. HIV Entry Inhibitors Virus-Cell Fusion gp41 gp120 V3 loop CD4 Binding CD4 Cell Membrane Coreceptor Binding CCR5/CXCR4 (R5/X4) CCR5 antagonists Enfuvirtide BMS-663068 Ibalizumab

39. Entry InhibitorAbb.Brand Name(s)Comments EnfuvirtideENF, T20 FuzeonFusion inhibitor; rarely used; twice-daily injections with injection site reactions MaravirocMVCSelzentryCCR5 antagonist; pre-treatment tropism testing required Entry Inhibitors

40. New Entry Inhibitors  Cenicriviroc (TBR-652): CCR5 antagonist with anti-CCR2 properties (anti-inflammatory)  BMS-663068: CD4 attachment inhibitor  Ibalizumab (TNX-355): Anti-CD4 monoclonal antibody; once weekly IV dosing

41. NRTIs

42. NRTIAbb.Brand Name(s)Comments ZidovudineAZT, ZDV Retrovir (Combivir, Trizivir), generic Rarely used DidanosineddIVidex, Videx EC, genericRarely used Stavudined4TZerit, genericRarely used Lamivudine3TCEpivir (Combivir, Trizivir, Epzicom), generic Typically used in combination with AZT or ABC AbacavirABCZiagen (Epzicom)Prescreen with HLA B*5701 Tenofovir DFTDFViread (Truvada, Atripla, Complera, Stribild) Monitor kidney function EmtricitabineFTCEmtriva (Truvada, Atripla, Complera, Stribild) Typically used in combination with TDF NRTIs

43. ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count CD4<50, RNA≥100K (n=98, 35 VF) CD4<50, RNA<100K (n=78, 23 VF) CD4 50 to <200, RNA≥100K (n=80, 19 VF) CD4 50 to <200, RNA<100K (n=153, 10 VF) CD4 200 to <350, RNA≥100K (n=39, 6 VF) CD4 200 to <350, RNA<100K (n=273, 28 VF) CD4≥350, RNA≥100K (n=23, 5 VF) CD4≥350, RNA<100K (n=184, 29 VF) ABC/3TCTDF/FTC 1.0 0.8 0.6 0.4 0.2 0.0 0 24 48 72 96 120 144 168 192 216 Weeks from Randomization Probability of Remaining free of Virologic Failure 1.0 0.8 0.6 0.4 0.2 0.0 0 24 48 72 96 120 144 168 192 216 Weeks from Randomization Probability of Remaining free of Virologic Failure CD4<50, RNA≥100K (n=80, 6 VF) CD4<50, RNA<100K (n=83, 17 VF) CD4 50 to <200, RNA≥100K (n=70, 9 VF) CD4 50 to <200, RNA<100K (n=158, 19 VF) CD4 200 to <350, RNA≥100K (n=55, 8 VF) CD4 200 to <350, RNA<100K (n=289, 29 VF) CD4≥350, RNA≥100K (n=20, 2 VF) CD4≥350, RNA<100K (n=173, 24 VF) Grant P, et al. CROI 2011. Abstract 535.

44. Abacavir and MI Risk: Recent published studies ReferenceStudy DesignIncreased risk? Choi, AIDS 2011, VAObservationalYes Bedimo, CID 2011, VAObservationalNo Durand, J AIDS 2011, MontrealObservationalYes Ribaudo, CID 2011, ACTGCohort from RCTsNo Cruciani, AIDS 2011Met-analysisNo Paul Sax “ How difficult it is to find a consensus can be exemplifiedby the fact that even identical data sources (Veterans Health Administration) analyzed by different investigators can lead to conflicting results …” Georg Behrens, AIDS 2011;2043-2045.

45. Abacavir and MI Risk Conflicting data from observational and prospective studies Proposed pathogenic models: –Inflammation –Increased platelet reactivity/adhesion –Impaired flow-mediated dilatation –Atherogenic lipid profile Guidelines: “use with caution” in patients with high CV risk DHHS Guidelines, October 14, 2011

46. VA Study: TDF and risk of kidney disease 10,841 HIV+ pts at VA Time to first occurrence of 1) proteinuria 2) rapid decline in kidney function and 3) CKD (eGFR rate < 60 ) Each year of exposure to TDF associated with: –34% increased risk of proteinuria (p < 0.0001) –11% increased risk of rapid decline (p = 0.0033) –33% increased risk of CKD (p < 0.0001). Pre-existing renal risk factors did not appear to worsen the effects of tenofovir. Scherzer R, et al. AIDS 2012 [Epub ahead of print]

47. Switch to TDF increases bone turnover and reduces bone mineral density Randomization group Continue AZT/3TCSwitch to TDF/FTC BMDMed. (IQR)Within group p-value Med. (IQR)Within group p-value Between group p-value Femoral neck1.36 (-3.26, 1.63) 0.74-1.52 (-3.04, 0.22) 0.160.48 Lumbar spine-0.18 (-2.35, 1.85) 0.91-2.04 (03.28, -0.40) 0.010.03 Subjects on AZT/3TC (n=54) randomized to continue or switch to TDF/FTC Markers of bone formation and bone resorption also increased in TDF/FTC group Cotter A, et al. Abstract 125LB, CROI 2012

48. Switching from TDF to RAL improves BMD Bloch, 2012

49. -2.0 -1.5 -0.5 0.0 0.5 Median VL Change (log 10 c/mL) 0 Tenofovir alafenamide fumarate (TAF): Tenofovir pro-drug with greater antiviral activity than TDF Higher intracellular tenofovir diphosphate levels and lower circulating plasma tenofovir levels with TAF vs TDF Ruane PJ, et al. CROI 2012. Abstract 103. Day 1020 Dosing Placebo (n = 7) TDF 300 mg (n = 6) TAF 8 mg (n = 9) TAF 25 mg (n = 8) TAF 40 mg (n = 8)

50. Zolopa, et al., CROI 2013;# 99LB E/C/F/TAF QD E/C/F/TDF Placebo QD ART-naive subjects (n=150) E/C/F/TDF QD E/C/F/TAF Placebo QD Week 48 Randomized 2:1 Stratification by VL >/≤100,000 Treatment Arm 1 (n=100) Treatment Arm 2 (n=50) Primary endpoint --Proportion with VL < 50 at Week 24 (Snapshot) GS-US-292-0101: E/C/F/TDF vs. E/C/F/TAF Phase 2 Study Design Randomized, placebo-controlled, double-blind study

51. Zolopa, et al., CROI 2013; Paper # 99LB GS-US-292-0101: Virologic Response (M=F, ITT), week 24 0 10 20 30 40 50 60 70 80 90 100 2 E/C/F/TAF (n=112) E/C/F/TDF (n=58) 48 12 1624 % Subjects with VL <50 (M=F, ITT) Time (Weeks) E/C/F/TAF 87.5% E/C/F/TDF 89.7%  Mean change from baseline CD4 count: –E/C/F/TAF, +163 –STB, +177 (p = 0.76)

52. Zolopa, et al., CROI 2013; Paper # 99LB GS-US-292-101: Median Change in Serum Creatinine through Week 24 0.09 0.06 0.11 0.12 0.10 0.12 0.08 0.05 0.08 0.06 0.08 0.07  Change in serum creatinine at Week 24 –E/C/F/TAF: 0.07 mg/dL –E/C/F/TDF: 0.12 mg/dL (p=0.02) p = 0.02

53. Zolopa, et al., CROI 2013; Paper # 99LB GS-US-292-102: Percent Change in Bone Mineral Density (DEXA) at Week 24 SPINE  Proportion of subjects with no decrease in BMD –Spine: E/C/F/TAF, 38%; E/C/F/TDF, 12% –Hip: E/C/F/TAF, 41%; E/C/F/TDF: 23% HIP - 0.8 - 2.5 - 0.3 - 2.0 p = 0.002 p < 0.001

54. Single tablet regimens PROSCONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects Teratogenicity Resistance with interruption Rash More lipid effects than others TDF/FTC/RPV Better tolerated than EFV Good switch data Recommended only if VL <100,000 Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers TDF/FTC/ EVG/COBI Non-inferior to TDF/FTC/ EFV Better tolerated than EFV COBI drug interactions COBI effect on eGFR

55. Single tablet regimens PROSCONS TDF/FTC/EFV PK forgiving of missed doses CNS side effects Teratogenicity Resistance with interruption Rash More lipid effects than others TDF/FTC/RPV Better tolerated than EFV Good switch data Recommended only if VL <100,000 Less forgiving of non-adherence More resistance with failure, including ETR cross-resistance Food requirement No PPI, caution with H2 blockers TDF/FTC/ EVG/COBI Non-inferior to TDF/FTC/ EFV Better tolerated than EFV COBI drug interactions COBI effect on eGFR ABC/3TC/DTG Only non-TDF-based STR Superior to TDF/FTC/EFV (better tolerability) Possible increased risk of MI with ABC

56. Why prescribe more than one tablet in 2013?  Boosted PI + 2 NRTIs: –Patients with unreliable adherence –Transmitted resistance –Pregnancy  RAL + 2 NRTIs: –Few drug interactions  ABC/3TC + 3 rd agent: –Kidney, bone disease  NRTI-sparing regimens: –Contrainidications to NRTIs –Baseline NRTI resistance

57. Choice of ART: Special populations and scenarios Pregnancy or likelihood of pregnancy Avoid EFV (1 st trimester) No data on newer agents (RPV, EVG/COBI) NRTIs: AZT/3TC, TDF/FTC PIs: LPV/r, ATV/r HCV coinfection RAL: can be used with telaprevir, boceprevir ATV: can be used with telaprevir EFV: requires higher dose telaprevir HBV coinfection TDF/FTC-based regimen if possible

58. Choice of ART: Special populations and scenarios Chronic kidney disease Avoid TDF (and ATV, LPV/r?) Pre-existing osteoporosis/osteopenia Avoid TDF Need for urgent ART without resistance data (primary HIV, acute OI) Boosted PI-based regimen

59. ART: New formulations  3 single-tablet regimens now available  3 more in development: –DTG/ABC/3TC –EVG/COBI/FTC/TAF (“E/C/F/TAF”) –DRV/COBI/FTC/TAF (“D/C/F/TAF”)  Other possible coformulations: –ATV/COBI –DRV/COBI –EVG/COBI –TAF/FTC

60. Treatment-Experienced Patients

61. Elvitegravir Comparable to Raltegravir in ART- Experienced Patients at Wk 96  CD4 gain: +205 (EVG) vs +198 (RAL) at Wk 96  Similar rates of treatment- emergent integrase resistance in each arm (7%)  Similar rates of AEs overall –More diarrhea with EVG vs RAL (13% vs 8%) –More liver-related AEs with RAL (1.7% vs 0.8%) Virologic Response Virologic Failure Elion R, et al. International AIDS Conference 2012. Abstract TUAB105. Others Patients, % 59 22 19 23 19 58 0 20 40 60 80 100 W48 48 26 45 29 26 W96 EVG (n = 351) RAL (n = 351) VL< 50 c/mL (ITT, TLOVR)

62. SAILING: Superior Virologic Suppression With DTG vs RAL at 24 Wks  Lower incidence of integrase resistance at VF with DTG –R263K at VF in 2 DTG pts; first report of treatment-emergent resistance on DTG –< 2-fold change in IC50 for both DTG and RAL –Y143, Q148, and/or N155 at VF in 9 RAL pts; consistent with previous studies –High-level resistance to RAL  Both regimens well tolerated with similar AE profiles Pozniak A, et al. CROI 2013. Abstract 179LB. VL < 50 c/mL (%) 100 80 60 40 20 0 BL 4 8 1216 24 Week Week 24 adjusted difference in response (95% CI): +9.7 in favor of DTG (3.1%, 15.9%); P =.003 79% 70% Dolutegravir + OBR Raltegravir + OBR

63. SECOND-LINE: Treatment options after failure of NNRTI + 2 NRTIs  541 patients failing initial therapy randomized to: –LPV/r + 2-3 NRTIs selected by genotype –LPV/r + RAL LPV/r + NRTs (N=271) LPVr + RAL (N=270) P VL <200219 (81%)223 (83%)0.59 VL <50191 (70%)192 (71%)0.56 CD4 increase 1141500.01 Boyd M, et al. CROI 2013. Abstract 180 LB

64. ACTG OPTIONS: Are NRTIs necessary in treatment-experienced patients? –360 pts failing ART w/ NRTI, NNRTI, and PI resistance or experience –Regimen chosen based on review of ART history, resistance, and tropism –PSS >2 required –Randomized to omit or include NRTIs –NRTIs not necessary if >2 active drugs included in regimen Omit NRTIs N=179 Include NRTIs N=181 Regimen failure through wk 4853 (30%)48 (26%) VL <50 at wk 4864%68% Severe signs/Sx or lab abnormality67 (38%)65 (35%) Tashima K, et al. CROI 2013. Abstract 153LB