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00002-E-1 – 1 December 2003 Anti-HIV drugs 2010-2011 Andrea De Luca, M.D. Institute of Clinical Infectious Diseases. Catholic University, Rome 2nd Division.

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Presentation on theme: "00002-E-1 – 1 December 2003 Anti-HIV drugs 2010-2011 Andrea De Luca, M.D. Institute of Clinical Infectious Diseases. Catholic University, Rome 2nd Division."— Presentation transcript:

1 00002-E-1 – 1 December 2003 Anti-HIV drugs 2010-2011 Andrea De Luca, M.D. Institute of Clinical Infectious Diseases. Catholic University, Rome 2nd Division of Infectious Diseases, University Hospital of Siena, Italy

2 CD4 + HIV RNA time HAART Mortality Opportunistic infections Goals of antiretroviral therapy

3 00002-E-3 – 1 December 2003 Probability (%) to develop full blown AIDS in the subsequent 3 years by CD4 counts and HIV RNA levels before and after the introduction of antiretroviral therapy Without therapy With therapy

4 00002-E-4 – 1 December 2003 New AIDS cases per year of diagnosis in Italy

5 Limitations of antiretroviral therapy morbidity and mortality but… l Eradication impossible because of latently infected CD4+ memory T cells l Emergence of drug resistance LIFE-LONG CHRONIC TREATMENT NECESSARY Tolerability Adherence

6 00002-E-6 – 1 December 2003 Antiviral potency and development of drug-resistance Antiviral potency Risk of development of drug-resistance poorsuboptimalhigh Poor pharmacokineticsSuboptimal adherence Drug pressure selects resistant virus Inadequate drug pressure to select resistant virus Complete viral suppression Increasing adherence

7 RT Provirus Proteins RNA DNA RNA DNA RT Viral regulatory proteins Viral protease Reverse transcriptase Viral integrase RNA Attachment, fusion and entry DNA Viral zinc-finger nucleocapsid proteins

8 00002-E-8 – 1 December 2003 Antiretroviral drugs and classes licensed for use in developed countries Nucleoside/nucle otide RT inhibitors Non-nucleoside RT inhibitors Protease inhibitors Fusion inhibitors Integrase inhibitors CCR5 antagonists ZidovudineNevirapineSaquinavir/ritEnfuvirtideRaltegravirMaraviroc DidanosineEfavirenz(Ritonavir) (Zalcitabine)(Delavirdine)Indinavir/rit LamivudineEtravirineNelfinavir StavudineFosamprenavir/(rit) AbacavirLopinavir/rit TenofovirAtazanavir/ (rit) EmtricitabineTipranavir/rit Darunavir/rit

9 00002-E-9 – 1 December 2003 NRTI l Historical ARV drugs. Still difficult to avoid l Essential component of ART regimens (2 NRTI+ x) l Alone: Low/intermediate potency, intermediate genetic barrier l Class-toxicity: mitochondrial toxicity (lipoatrophy, peripheral neuropathy, pancreatitis, hyperlipemia) l Individual components related to organ-specific toxicities (bone marrow, renal/bone, cardiovascular)

10 00002-E-10 – 1 December 2003 NNRTI l High potency, low genetic barrier to resistance (except 2nd generation) l Toxicity: cutaneous (rash, SJS), liver, lipid (modest) l Individual components: organ-specific (EFV: CNS, teratogenicity; NVP: liver)

11 00002-E-11 – 1 December 2003 PI l Potent, high genetic barrier (ritonavir-boosted) l Class-toxicity: metabolism (lipid, glicidic, lipodystrophy, cardiovascular) l Ritonavir toxicity (gastrointestinal, lipids) l Lopinavir and fosamprenavir probably cause diarrhea per se l Specific toxicities: hyperbilirubinemia (atazanavir), cutaneous reactions (sulpha component of fosamprenavir and darunavir), nephrolithiasis (indinavir>atazanavir)

12 00002-E-12 – 1 December 2003 FI, INSTI, CCR5 antagonists l All potent drugs but low/intermediate genetic barrier to resistance l FI: injection site reactions l Other drugs: very modest toxicity –Raltegravir: CNS/psychiatric, muscle –Maraviroc: liver

13 00002-E-13 – 1 December 2003 ART: Recent /Future developments l Goal (virologic suppression) achieved in 85-90% of patients in trials and clinical practice (drug naive and experienced patients) l Towards more simple regimens (one pill/day) l Increased genetic barrier l Improved tolerability l Further improvements: –Less medium-long term toxicity (metabolic, cardiovascular, renal/bone) –PK boosting without ritonavir

14 00002-E-14 – 1 December 2003 New treatments and strategies for naive patients

15 00002-E-15 – 1 December 2003 ARTEMIS: Wk 96 Lipid and Anthropometric Substudy l Randomized noninferiority trial of DRV/RTV vs LPV/RTV, both with TDF/FTC, in naive pts –DRV/RTV noninferior to LPV/RTV at Wk 48. At Wk 96, DRV/RTV met superiority criteria vs LPV/RTV l In anthropometric analysis at Wk 96, no increase in median midwaist:midhip ratio in either study arm l Changes in BMI, body weight, midwaist, chest, hip, and circumferences similar between arms and not clinically relevant DRV/RTV LPV/RTV TC LDL-C HDL-C TG 0 10 20 30 40 50 26 35 17 15 5 8 18 56 Median Increase at Wk 96 (mg/dL) Baraldi E, et al. IAS 2009. Abstract MOPEB034. l Statistically greater % increases in TC, TG in LPV/RTV arm than DRV/RTV arm (P <.001) 60

16 00002-E-16 – 1 December 2003 STARTMRK: Metabolic, Body Composition Changes at Wk 96 With RAL vs EFV DeJesus E, et al. CROI 2010. Abstract 720. Adapted with permission of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved. Mean Change (mg/dL) 0 40 50 20 30 10 -10 TCHDL-CLDL-CTG Glucose Appendicular Fat Mean Percent (SE) Change 40 20 30 10 0 04896 Wks 564638 554037 EFV RAL Contributing Patients, n 18.1 17.7 17.0 18.2 P <.001 P =.025 RAL EFV

17 00002-E-17 – 1 December 2003 MERIT: Wk 96 Response With MVC vs EFV in Naive Pts MERIT-ES: reanalysis of MERIT trial using enhanced phenotypic tropism assay suggested noninferiority of MVC to EFV when additional pts with D/M-tropic virus identified by enhanced assay excluded [1] Wk 96 efficacy analysis included only MERIT-ES population [2] Similar proportions in MVC and EFV with VL < 50 copies/mL at Wk 96 CD4+ increase at Wk 96 greater with MVC vs EFV (+212 vs +171 cells/mm³) EFV more likely discontinued for AEs: 15.5% vs 6.1% on MVC MVC more likely discontinued for insufficient response: 12.5% vs 5.9% on EFV EFV + ZDV/3TCMVC + ZDV/3TC MERITMERIT-ES 0 20 40 60 80 100 HIV-1 RNA < 50 c/mL (%) 69.3 65.3 68.3 68.5 Wk 48 62.4 58.5 Wk 96 MERIT-ES 60.7 60.5 n 361 360 303 311 203 210 303 311 ITT, NC = FModified ITT TLOVR 1. Saag M, et al. ICAAC/IDSA 2008. Abstract 1232a. 2. Heera J, et al. IAS 2009. Abstract TUAB103. 3. Nelson M, et al. IAS 2009. Abstract MOPEB040. Higher levels of dyslipidemia on EFV 5/15 pts who discontinued EFV for tolerability developed NNRTI mutations in follow-up [3]

18 00002-E-18 – 1 December 2003 Rilpivirine 25 mg QD + TDF/FTC 300/200 mg QD (n = 346) EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 344) *THRIVE only. Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC. Stratification by BL HIV-1 RNA < 100,000 vs 100,000 copies/mL, NRTI use* Wk 96 final analysis Wk 48 primary analysis Rilpivirine 25 mg QD + 2 NRTIs (n = 340) EFV 600 mg QD + 2 NRTIs (n = 338) ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients l Randomized, double-blind phase III trials Cohen C, et al. AIDS 2010. Abstract THLBB206. ECHO (N = 690) THRIVE (N = 678) Treatment-naive, HIV-1 RNA 5000 copies/mL no NNRTI RAMs, susceptible to NRTIs

19 00002-E-19 – 1 December 2003 ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48 *P <.0001 for noninferiority at -12% margin. RilpivirineEFV Cohen C, et al. AIDS 2010. Abstract THLBB206. Graphics used with permission. HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL 40 0 100 20 80 82.3 84.3 60 682686n = ECHOTHRIVEPooled Patients (%) 82.8 82.9 81.7 85.6 338340344346 -3.6 (-9.8 to +2.5) 6.6 (1.6-11.5) > 100,000 copies/mL 125/ 165 121/ 153 246/ 318 149/ 181 136/ 171 285/ 352 77 81 79 80 76 82 Patients (%) 40 0 100 20 80 60 PooledTHRIVE ECHO 100,000 copies/mL 162/ 181 170/ 187 332/ 368 136/ 163 140/ 167 276/ 330 90 83 91 84 90 84 Patients (%) 40 0 100 20 80 60 ECHOTHRIVEPooled

20 00002-E-20 – 1 December 2003 ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events Wk 48 OutcomeRilpivirine (n = 686) Efavirenz (n = 682) VF with resistance data, n6228 No NNRTI or NRTI RAMs,%2943 1 Emergent NNRTI RAM,% 6354 Most frequent NNRTI RAME138KK103N 1 Emergent NRTI RAMs, % 6832 Most frequent NRTI RAMM184IM184V Cohen C, et al. AIDS 2010. Abstract THLBB206. Table used with permission. Treatment Failure in ECHO and THRIVE Adverse Events and Discontinuation Resistance at Virologic Failure 6 0 15 3 12 9 4.8 346 n = VF 9.0 682686 6.7 AE 2.0 682686 Patients (%) Wk 48 Outcome, %Rilpivirine (n = 686) Efavirenz (n = 682) P Value DC for AE38.0005 Most Common AEs of Interest, % Any neurologic AE1738<.0001 Any psychiatric AE1523.0002 Any rash314<.0001 Rilpivirine EFV

21 00002-E-21 – 1 December 2003 GS-9350–Boosted Elvitegravir + FTC/TDF Noninferior to EFV/FTC/TDF in Naive Pts Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission. Wk 24 stratum-weighted difference: +5% (95% CI: -11.0% to 21.1%) HIV-1 RNA < 50 c/mL (%) 100 80 60 40 20 0 Wk 04812162024 GS-9350/EVG/FTC/TDF EFV/FTC/TDF 83 90 ITT, M = F l Cobicistat (GS-9350): investigational CYP3A inhibitor (boosting agent) GS-9350/EVG/FTC/TDF (n = 48) EFV/FTC/TDF (n = 23) Treatment-naive pts with CD4+ 50 cells/mm 3, HIV-1 RNA 5000 c/mL, no NRTI, NNRTI, or PI resistance (N = 71) Wk 24 primary endpoint analysis Wk 48 Elvitegravir: investigational integrase inhibitor

22 00002-E-22 – 1 December 2003 GS-9350–Boosted ATV Virologic Efficacy Similar to ATV/RTV in Naive Pts Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission. Wk 24 stratum-weighted difference: - 1.9% (95% CI: -18.4% to 14.7%) HIV-1 RNA < 50 c/mL (%) GS-9350–Boosted ATV + FTC/TDF (n = 50) RTV-Boosted ATV + FTC/TDF (n = 29) Treatment-naive pts with CD4+ 50 cells/mm 3, HIV-1 RNA 5000 c/mL, no NRTI, NNRTI, or PI resistance (N = 79) Wk 24 primary endpoint Wk 48 100 80 60 40 20 0 Wk 04812162024 RTV GS-9350 86 84 ITT, M = F l Phase II study comparing cobicistat (GS-9350) vs ritonavir as boosting agent for atazanavir

23 00002-E-23 – 1 December 2003 Wk 16 Treatment naive, HIV-1 RNA > 1000 copies/mL, no CD4+ cell count restriction (N = 205) *NRTIs individually selected by trial investigators (TDF/FTC, 67%; ABC/3TC, 33%). After Wk 48, all patients continue at dose selected for phase III trial. S/GSK1349572 10 mg QD + 2 NRTIs QD* (n = 53) S/GSK1349572 25 mg QD + 2 NRTIs QD* (n = 51) S/GSK1349572 50 mg QD + 2 NRTIs QD* (n = 51) EFV 600 mg QD + 2 NRTIs QD* (n = 50) Arribas J, et al. AIDS 2010. Abstract THLBB205. Dose-ranging, partially blinded phase IIb trial Wk 48 SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients

24 00002-E-24 – 1 December 2003 SPRING-1: Virologic Response to S/GSK1349572 vs EFV at Wk 16 l CD4+ cell count increases 153-176 cells/mm³ on S/GSK1249572 vs 116 cells/mm 3 on EFV l No serious adverse events related to S/GSK1349572 Arribas J, et al. AIDS 2010. Abstract THLBB205. Graphic used with permission. Wks HIV-1 RNA < 50 copies/mL (TLOVR), % 96% 92% 90% 60% Time to < 50 copies/mL shorter for S/GSK1349572 dose than EFV (P <.001 for each comparison) 100 80 60 40 20 0 BL12481216 50-mg dose chosen for phase III trial 572 10 mg 572 25 mg 572 50 mg EFV 600 mg

25 00002-E-25 – 1 December 2003 ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts l NVP either once daily or twice daily noninferior to ATV/RTV at Wk 48 l Rates of AEs similar overall but higher rate of discontinuation due to toxicity in NVP arms (13.6% vs 3.6%) HIV-1 RNA < 50 c/mL at Wk 48 (%) 40 0 100 20 80 Any NVP 65.3 66.8 60 P =.63 ITT, NC = F NVP QD NVP BID 67.0 66.5 Outcome at Wk 48, % NVP QD (n = 188) NVP BID (n = 188) ATV/RTV (n = 193) Virologic failure11.212.814.0 Investigator- defined virologic failure 5.911.21.6 No confirmed response at Wk 48 5.31.612.4 Soriano V, et al. IAS 2009. Abstract LBPEB07. ATV/ RTV n = 376193188

26 00002-E-26 – 1 December 2003 VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48 l Multicenter, randomized, double-blind, noninferiority study in treatment-naive patients – NVP XR 400 mg QD (n = 508) vs – NVP IR 200 mg BID (n = 505) – Both combined with TDF/FTC l Inclusion criteria – HIV-1 RNA > 1000 copies/mL – CD4+ cell count < 400 cells/mm 3 if male or < 250 cells/mm 3 if female l Similar safety and tolerability for both arms l AEs included –Stevens-Johnson (n = 5) –Hepatitis (n = 14) –Rash (n = 21) 0 20 40 60 80 100 Patients (%) NVP IRNVP XR 81.0 75.9 HIV-1 RNA < 50 copies/mL (TLOVR) Gathe J, et al. AIDS 2010. Abstract THLBB202. Adjusted difference 4.92% (95% CI: -0.11 to 9.96)

27 00002-E-27 – 1 December 2003 PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients Randomized, open-label, multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mL – LPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vs – LPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105) l Relatively low mean baseline HIV-1 RNA – 4.25 log 10 copies/mL Reynes J, et al. AIDS 2010. Abstract MOAB0101. Graphic used with permission. Similar CD4+ cell count gain at Wk 48 – LPV/RTV + RAL: 215 cells/mm³ – LPV/RTV + NRTIs: 245 cells/mm³ 0 20 40 60 80 100 Wks 0 HIV-1 RNA < 40 copies/mL (ITT-TLOVR) 81624324048 83.2% 84.8% Difference: -1.6% (95% CI: -12.0% to 8.8%) *Statistically significant difference between arms: Wks 2, 4, 8 P <.002 Wk 16 P =.038 * * * * Patients (%) LPV/RTV + RAL

28 00002-E-28 – 1 December 2003 l Mean increases in TC, TG, and HDL-C from BL to Wk 48 significantly greater in RAL arm vs NRTI arm Reynes J, et al. AIDS 2010. Abstract MOAB0101. Resistance Development at VF LPV/RTV + RAL LPV/RTV + NRTIs Met criteria for resistance testing 43 INSTI mutation (N155H) 10 NRTI mutations (M184V) 01 0 20 40 60 80 100 TCTGHDL-C Mean Change From BL, mg/dL +46 +29 +99 +59 +12 +8 P =.008 P =.044 P =.015 LPV/RTV + RALLPV/RTV + NRTIs PROGRESS: Lipids and Adverse Events at Wk 48 l Grade 3/4 laboratory events did not differ between arms, except higher risk of CPK > 4 x ULN in RAL arm –12.9% vs 3.8% (P =.023)

29 00002-E-29 – 1 December 2003 A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTCWk 24 Interim Analysis l CD4 + cell count increases similar –ATV/RTV + MVC: 195 cells/mm³ –ATV/RTV + TDF/FTC: 173 cells/mm³ l Grade 3/4 hyperbilirubinemia –ATV/RTV + MVC: 59.3% –ATV/RTV + TDF/FTC: 49.2% l 5 patients in MVC arm, 1 patient in TDF/FTC arm switched to DRV/RTV per protocol for jaundice or scleral icterus Mills A, et al. AIDS 2010. Abstract THLBB203. 40 0 100 20 80 HIV-1 RNA < 100K 95 80 60 77 81 HIV-1 RNA 100K HIV-1 RNA < 50 copies/mL Overall and by BL VL 22163944 Overall 89 80 61 60 Patients (%) n = ATV/RTV + MVC ATV/RTV + TDF/FTC

30 00002-E-30 – 1 December 2003 SPARTAN: Pilot Study of ATV + RAL vs ATV/RTV + TDF/FTC in Naive Pts l Randomized, noncomparative, open- label, multicenter pilot study in treatment-naive patients with HIV-1 RNA 5000 copies/mL –ATV 300 mg BID + RAL 400 mg BID (n = 63) vs –ATV/RTV 3001/00 mg QD + TDF/FTC 300/200 mg QD (n = 31) l Mean BL HIV-1 RNA: 4.9 log 10 copies/mL Kozal MJ, et al. AIDS 2010. Abstract THLBB204. Graphic used with permission. Wks 0 20 40 60 80 100 BL4812162024 Patients (%) 74.6% 63.3% Primary Endpoint: HIV-1 RNA < 50 copies/mL Through Wk 24 (CVR*, NC = F) ATV BID + RAL BID ATV/RTV QD + TDF/FTC *CVR = modified ITT.

31 00002-E-31 – 1 December 2003 SPARTAN: Wk 24 Results l No significant changes in fasting lipids observed in either arm during study period l Trial terminated at Wk 24 due to resistance data and grade 4 bilirubin abnormalities (21%) with experimental regimen vs control arm (0%) Resistance Through Wk 24, n ATV + RAL (n = 63) ATV/RTV + TDF/FTC (n = 30) Virologic failure (HIV-1 RNA > 50 copies/mL) 118 BL HIV-1 RNA > 250,000 copies/mL 84 Evaluable for resistance testing * (HIV-1 RNA > 400 copies/mL) 61 Genotypic and phenotypic RAL resistance N155H2NA Q148R1NA Q148R + N155H + T97A1NA Phenotypic RAL resistance without genotypic evidence of resistance 1NA ATV resistance00 TDF/FTC resistanceNA0 Kozal MJ, et al. AIDS 2010. Abstract THLBB204. *Criteria for resistance testing: HIV-1 RNA 400 copies/mL at or after Wk 24 Rebound to HIV-1 RNA 400 any time during the study Discontinued before achieving HIV-1 RNA < 50 copies/mL after Wk 8 with last HIV RNA 400 copies/mL

32 00002-E-32 – 1 December 2003 SENSE: EFV vs ETR in Treatment-Naive Patients l Randomized, double-blind trial of treatment- naive patients with HIV-1 RNA > 5000 copies/mL –EFV 600 mg QD (n = 78) vs –ETR 400 mg QD (n = 79) –Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC) l Primary endpoint: % of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric AEs at Wk 12 l Mean change in HIV-1 RNA at Wk 12 similar between arms (-2.9 log 10 copies/mL) l More drug-related neuropsychiatric AEs in EFV arm vs ETR arm 40 0 100 20 80 46 17 60 17 5 Grade 1-4Grade 2-4 EFVETREFVETR 10 patients discontinued in ETR and 8 in EFV arm by Wk 12 Gazzard B, et al. AIDS 2010. Abstract LBPE19. Drug-Related Neuropsychiatric AEs Patients (%) P <.001P =.02

33 00002-E-33 – 1 December 2003 Switch/simplification studies

34 00002-E-34 – 1 December 2003 BL HIV-1 RNA < 100,000 c/mL BL HIV-1 RNA 100,000 c/mL ATV (n = 210) ATV/RTV (n = 209) Squires K, et al. IAS 2009. Abstract WELBB103. Graphic used with permission. HIV-1 RNA < 50 c/mL at Wk 84 (%) Overall Results 0 20 40 60 80 100 86 80.8 85 79 87 82 ARIES: Boosted vs Unboosted ATV Maintenance: Wk 84 Results

35 00002-E-35 – 1 December 2003 SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens 0 20 40 60 80 100 Patients (%) Switch to RAL Continue PI/RTV 86.6 89.2 Free of Treatment Failure at Wk 48 (ITT, S = F) Patients With VF RAL (n = 4) PI/RTV (n = 6) Prior VF13 Prior suboptimal ART23 Prior resistance mutations15 Resistance test at VF14 Mutations03 (PR, RT) Martinez E, et al. AIDS. 2010;24:1697-1707. Mean Change From Baseline to Wk 48, % Switch to RAL Continue PI/RTV P Value Triglycerides-22.1+4.7<.0001 TC-11.2+1.8<.0001 LDL-C-6.5+3.0<.001 HDL-C-3.2+5.8<.0001 Total to HDL-C ratio -4.9-1.3<.05

36 00002-E-36 – 1 December 2003 MONET Trial: 96-Wk Efficacy Results of Switch to DRV/RTV Monotherapy l Randomized, open-label trial of switch to DRV/RTV monotherapy vs continuing DRV/RTV HAART in virologically suppressed pts l DRV/RTV monotherapy noninferior vs DRV/RTV HAART at Wk 48 [1] l Monotherapy NOT noninferior with switch = failure analysis at Wk 96 [2] –Δ -5.8% (95% CI: -16.0% to +4.4%) l If resuppression with intensification included as success, then monotherapy noninferior at Wk 96 –Δ +1.4% (95% CI: -5.5% to +8.3%) 1. Arribas JR, et al. IAS 2009. Abstract TUAB106LB. 2. Rieger A, et al. AIDS 2010. Abstract THLBB209. HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%) 40 0 100 20 80 Wk 48 [1] 85.3 84.3 60 DRV/RTV monotherapy (n = 127) DRV/RTV + 2 NRTIs (n = 129) 80.6 74.8 Wk 96 [2] Switch = failure 92.1 90.7 Switch allowed

37 00002-E-37 – 1 December 2003 Treatment-experienced individuals

38 00002-E-38 – 1 December 2003 % 48w 96w Evolving efficacy of antiretroviral regimens in multiexperienced patients (percent <50 copies/ml)

39 00002-E-39 – 1 December 2003 Pooled DUET 96-Wk Results: ETR + DRV/RTV- Containing OBR in Expd Pts HIV-1 RNA < 50 c/mL (%) (ITT-TLOVR) 40 0 100 20 80 P <.0001 Wk 48Wk 96 39 60 36 57 60 P <.0001 l Randomized trial of ETR vs placebo, both with DRV/RTV-containing OBR in multiclass- resistant pts –Superior virologic suppression with ETR at Wks 24 (primary endpoint) and 48 l Superior virologic suppression maintained at Wk 96 in ETR vs placebo arm [1] –Higher response with ETR irrespective of number of active agents, baseline ETR FC, weighted score, sex, race, and age l Greater mean change in CD4+ cell count with ETR vs placebo –+123 vs +86 cells/mm³ (P <.0001) l No new safety signals in Wks 48-96 [2] –New rash in < 1% of pts –CNS adverse effects similar between arms in Wks 48- 96 ETR (n = 599) Placebo (n = 604) 1. Mills A, et al. IAS 2009. Abstract MOPEB036. 2. Nelson T, et al. IAS 2009. Abstract MOPEB038.

40 00002-E-40 – 1 December 2003 ODIN: QD vs BID Darunavir/Ritonavir + OBR in Treatment-Experienced Patients Cahn P, et al. CROI 2010. Abstract 57. QD DRV/RTV 800/100 mg + OBR* (n = 294) Treatment-experienced adults with stable HAART for 12 wks, HIV-1 RNA > 1000 copies/mL, CD4+ > 50 cells/mm 3, no DRV RAMs (N = 590) Wk 48 *OBR included 2 active NRTIs. Stratified by baseline HIV-1 RNA and > 50,000 copies/mL BID DRV/RTV 600/100 mg + OBR* (n = 296) Primary PI mutations in < 2% of patients in either arm

41 00002-E-41 – 1 December 2003 ODIN: HIV-1 RNA < 50 copies/mL at Wk 48 Overall and by Screening HIV-1 RNA l Similar CD4+ cell count increase between arms –QD DRV/RTV : +100 cells/mm 3 –BID DRV/RTV : +94 cells/mm 3 Cahn P, et al. CROI 2010. Abstract 57. Reproduced with permission. 100 Pts With HIV-1 RNA < 50 copies/mL (%) 80 60 20 0 012243648 40 84 Wks Difference in response, QD vs BID: ITT = 1.2% (95% CI: -6.1%, 8.5%) QD DRV/RTV 800/100 mg BID DRV/RTV 600/100 mg 72.1 70.9 100 Pts With HIV-1 RNA < 50 copies/mL (%) 80 60 20 0 50,000 40 Screening HIV-1 RNA (copies/mL) > 50,000 78.4 76.8 52.8 n =22222472

42 00002-E-42 – 1 December 2003 ODIN: Virologic Failure Not Statistically Different Between Arms Resistance Emergence in Pts With Virologic Failure and Paired Genotypes/Phenotypes QD DRV/RTV + OBRBID DRV/RTV + OBR Development of new RAMs,* n (%) Primary PI1 (1.7)0 Any PI7 (11.7)4 (9.5) Loss of susceptibility, n (%) Darunavir1 (1.7)0 Any PI2 (3.4)0 Cahn P, et al. CROI 2010. Abstract 57. *Patients with paired baseline/endpoint genotypes evaluated (n = 60 in QD arm and n = 42 in BID arm). Patients with paired baseline/endpoint phenotypes evaluated (n = 59 in QD arm and n = 41 in BID arm).

43 00002-E-43 – 1 December 2003 ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID Cahn P, et al. CROI 2010. Abstract 57. AEs,* %QD DRV/RTV + OBR (n = 294) BID DRV/RTV + OBR (n = 296) P Value Serious AEs5.49.1 -- Grade 2-4 treatment- emergent laboratory abnormalities* Total cholesterol 10.120.6 <.0007 LDL-C 9.816.7 <.019 Triglycerides5.211.0 <.014 *No significant differences in grade 3/4 AEs, AEs leading to treatment discontinuation, GI AEs, ALT levels, or AST levels.

44 00002-E-44 – 1 December 2003 VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients l International, multicenter, single-arm, phase II study in 27 patients with RAL resistance –S/GSK572 50 mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapy –Day 11-Wk 24: S/GSK572 50 mg QD continued and regimen optimized –Median fold-change in RAL susceptibility at BL: 161 (range: 0.6 - > 166) –Median S/GSK572 FC at BL: 1.5 (range: 0.6-35) l Stratified by BL integrase genotype –Group 1: Q148 + 1 secondary resistance mutations (n = 9) –Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18) HIV-1 RNA Response at Day 11 Group 1 (n = 9) Group 2 (n = 18) < 400 c/mL or 0.7 log 10 c/mL decline, % 33100 Change from baseline, log 10 c/mL -0.72-1.82 Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P <.001) Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutations –In 17 subjects, < 2 FC in susceptibility –In 1 subject, ~ 6 FC in susceptibility Eron J, et al. AIDS 2010. Abstract MOAB0105.

45 00002-E-45 – 1 December 2003 Resource-limited settings/special populations

46 ART in special populations: patients starting TB therapy for active disease CD4 cell count recommendationType of ART/comments <350 Recommend ART as soon as TB treatment tolerated EFV-based > NVP >350 Recommend ART as soon as TB treatment tolerated (data insufficient) EFV-based >NVP unavailableRecommend ART as soon as TB treatment tolerated EFV-based >NVP

47 00002-E-47 – 1 December 2003 SAPiT: Optimal Time to Initiate ART in HIV/TB- Coinfected Patients Early ART ART initiated during intensive or continuation phase of TB therapy (n = 429) Sequential ART ART initiated after TB therapy completed (n = 213) HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm 3 (N = 642) Primary endpoint: all-cause mortality

48 00002-E-48 – 1 December 2003 Abdool Karim SS, et al. CROI 2009. Abstract 36a. Graphic reproduced with permission. 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Survival Months Postrandomization 0123456789101112131415161718192021222324 Intensive phase of TB treatment Post-TB treatment Continuation phase of TB treatment Early ART Sequential ART SAPiT: Increased Survival With Concurrent HIV and TB Treatment

49 00002-E-49 – 1 December 2003 CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients (CD4<200) l Significantly higher incidence of IRIS with early vs late HAART –4.03 vs 1.44 per 100 person-mos, respectively (P <.0001) Blanc FX, et al. AIDS 2010. Abstract THLBB206. Graphic used with permission.. Wk Survival Probability, % (95% CI) P Early ArmLate Arm 50 86.1 (81.8-89.4) 80.7 (76.0-84.6).07 100 82.6 (78.0-86.4) 73.0 (67.7-77.6).006 150 82.0 (77.2-85.9) 70.2 (64.5-75.2).002 FactorMultivariate Adjusted HR (95% CI) P Late therapy1.52 (1.12-2.05).007 BMI 161.68 (1.07-2.63).01 Karnofsky score 40 4.96 (2.42-10.16)<.001` Pulmonary + extrapulmonary TB 2.26 (1.62-3.16) <.001 NTM2.84 (1.13-7.13)<.001 MDR-TB8.02 (4.00-16.07)<.001 Factors Independently Associated With Mortality Survival Probability, Early vs Late Therapy Log rank P =.0042 Wks From TB Treatment Initiation Probability of Survival 1.00 0.90 0.80 0.70 0.60 Early arm wk 2 Late arm wk 8 050100150200250

50 00002-E-50 – 1 December 2003 ART in special populations: pregnant women l Primarily consider mothers need of ART and act accordingly (same as guidelines for adults) l Used to prevent mother-to-infant transmission as well l Avoid EFV in first trimester (teratogenic) l Prevention of MTCT: conflicting data on pros and cons of single dose NVP to mother and infant (negligible reduction in transmission in mothers who breastfeed, selection of resistance to non-nucleosidic RT inhibitors); same applies to other suboptimal therapies

51 00002-E-51 – 1 December 2003 BAN Study: Both Regimens Equally Effective at Preventing Transmission l Maternal HAART and infant NVP regimens both significantly reduced HIV-1 transmission by breastfeeding to infants at Wk 28 l Grade 3/4 adverse events generally comparable across arms, except –Significantly higher rate of neutropenia in women on maternal HAART vs control arm (6.7% vs 2.0%; P <.0001) –Substantially higher number of hypersensitivity reactions in infants on NVP vs control arm (16 vs 0 events) Age (Wks) Estimated Probability of Being HIV Positive 1481216202428 0.00 0.02 0.04 0.06 0.08 Control vs maternal HAART: P =.0032 Control vs infant NVP: P <.0001 Maternal HAART vs infant NVP: P =.1203 6.4% 3.0% 1.8% Chasela C, et al. IAS 2009. Abstract WELBC103.Graphic used with permission.. Control Maternal HAART Infant NVP

52 00002-E-52 – 1 December 2003 WHO 2009 recommendations for PMTCT in mothers who do not need ART for their own health


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