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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 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 Median Increase at Wk 96 (mg/dL) Baraldi E, et al. IAS 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 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) TCHDL-CLDL-CTG Glucose Appendicular Fat Mean Percent (SE) Change Wks EFV RAL Contributing Patients, n 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 HIV-1 RNA < 50 c/mL (%) Wk Wk 96 MERIT-ES n ITT, NC = FModified ITT TLOVR 1. Saag M, et al. ICAAC/IDSA Abstract 1232a. 2. Heera J, et al. IAS Abstract TUAB Nelson M, et al. IAS 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 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 Abstract THLBB206. Graphics used with permission. HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL n = ECHOTHRIVEPooled Patients (%) (-9.8 to +2.5) 6.6 ( ) > 100,000 copies/mL 125/ / / / / / Patients (%) PooledTHRIVE ECHO 100,000 copies/mL 162/ / / / / / Patients (%) 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,% Emergent NNRTI RAM,% 6354 Most frequent NNRTI RAME138KK103N 1 Emergent NRTI RAMs, % 6832 Most frequent NRTI RAMM184IM184V Cohen C, et al. AIDS Abstract THLBB206. Table used with permission. Treatment Failure in ECHO and THRIVE Adverse Events and Discontinuation Resistance at Virologic Failure n = VF AE Patients (%) Wk 48 Outcome, %Rilpivirine (n = 686) Efavirenz (n = 682) P Value DC for AE Most Common AEs of Interest, % Any neurologic AE1738<.0001 Any psychiatric AE 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 Abstract 58LB. Reproduced with permission. Wk 24 stratum-weighted difference: +5% (95% CI: -11.0% to 21.1%) HIV-1 RNA < 50 c/mL (%) Wk GS-9350/EVG/FTC/TDF EFV/FTC/TDF 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 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 Wk RTV GS 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/GSK mg QD + 2 NRTIs QD* (n = 53) S/GSK mg QD + 2 NRTIs QD* (n = 51) S/GSK mg QD + 2 NRTIs QD* (n = 51) EFV 600 mg QD + 2 NRTIs QD* (n = 50) Arribas J, et al. AIDS Abstract THLBB205. Dose-ranging, partially blinded phase IIb trial Wk 48 SPRING-1: S/GSK vs EFV in Treatment-Naive Patients

24 00002-E-24 – 1 December 2003 SPRING-1: Virologic Response to S/GSK vs EFV at Wk 16 l CD4+ cell count increases cells/mm³ on S/GSK vs 116 cells/mm 3 on EFV l No serious adverse events related to S/GSK Arribas J, et al. AIDS 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/GSK dose than EFV (P <.001 for each comparison) BL mg dose chosen for phase III trial mg mg 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 (%) Any NVP P =.63 ITT, NC = F NVP QD NVP BID Outcome at Wk 48, % NVP QD (n = 188) NVP BID (n = 188) ATV/RTV (n = 193) Virologic failure Investigator- defined virologic failure No confirmed response at Wk Soriano V, et al. IAS Abstract LBPEB07. ATV/ RTV n =

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) Patients (%) NVP IRNVP XR HIV-1 RNA < 50 copies/mL (TLOVR) Gathe J, et al. AIDS Abstract THLBB202. Adjusted difference 4.92% (95% CI: 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 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 Wks 0 HIV-1 RNA < 40 copies/mL (ITT-TLOVR) % 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 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) TCTGHDL-C Mean Change From BL, mg/dL 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 A : 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 Abstract THLBB HIV-1 RNA < 100K HIV-1 RNA 100K HIV-1 RNA < 50 copies/mL Overall and by BL VL Overall 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 Abstract THLBB204. Graphic used with permission. Wks BL 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 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 Grade 1-4Grade 2-4 EFVETREFVETR 10 patients discontinued in ETR and 8 in EFV arm by Wk 12 Gazzard B, et al. AIDS 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 Abstract WELBB103. Graphic used with permission. HIV-1 RNA < 50 c/mL at Wk 84 (%) Overall Results 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 Patients (%) Switch to RAL Continue PI/RTV 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: Mean Change From Baseline to Wk 48, % Switch to RAL Continue PI/RTV P Value Triglycerides <.0001 TC <.0001 LDL-C <.001 HDL-C <.0001 Total to HDL-C ratio <.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 Abstract TUAB106LB. 2. Rieger A, et al. AIDS Abstract THLBB209. HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%) Wk 48 [1] DRV/RTV monotherapy (n = 127) DRV/RTV + 2 NRTIs (n = 129) Wk 96 [2] Switch = failure 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) P <.0001 Wk 48Wk 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 [2] –New rash in < 1% of pts –CNS adverse effects similar between arms in Wks ETR (n = 599) Placebo (n = 604) 1. Mills A, et al. IAS Abstract MOPEB Nelson T, et al. IAS 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 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 Abstract 57. Reproduced with permission. 100 Pts With HIV-1 RNA < 50 copies/mL (%) 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 Pts With HIV-1 RNA < 50 copies/mL (%) , Screening HIV-1 RNA (copies/mL) > 50, n =

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 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 Abstract 57. AEs,* %QD DRV/RTV + OBR (n = 294) BID DRV/RTV + OBR (n = 296) P Value Serious AEs Grade 2-4 treatment- emergent laboratory abnormalities* Total cholesterol <.0007 LDL-C <.019 Triglycerides <.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/GSK in RAL-Resistant Patients l International, multicenter, single-arm, phase II study in 27 patients with RAL resistance –S/GSK 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/GSK mg QD continued and regimen optimized –Median fold-change in RAL susceptibility at BL: 161 (range: > 166) –Median S/GSK572 FC at BL: 1.5 (range: ) l Stratified by BL integrase genotype –Group 1: Q 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, % Change from baseline, log 10 c/mL 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 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 Abstract 36a. Graphic reproduced with permission Survival Months Postrandomization 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 Abstract THLBB206. Graphic used with permission.. Wk Survival Probability, % (95% CI) P Early ArmLate Arm ( ) 80.7 ( ) ( ) 73.0 ( ) ( ) 70.2 ( ).002 FactorMultivariate Adjusted HR (95% CI) P Late therapy1.52 ( ).007 BMI ( ).01 Karnofsky score ( )<.001` Pulmonary + extrapulmonary TB 2.26 ( ) <.001 NTM2.84 ( )<.001 MDR-TB8.02 ( )<.001 Factors Independently Associated With Mortality Survival Probability, Early vs Late Therapy Log rank P =.0042 Wks From TB Treatment Initiation Probability of Survival Early arm wk 2 Late arm wk

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 Control vs maternal HAART: P =.0032 Control vs infant NVP: P <.0001 Maternal HAART vs infant NVP: P = % 3.0% 1.8% Chasela C, et al. IAS 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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