BHIVA Best of CROI Feedback Meetings. London Birmingham North West England Cardiff Gateshead Edinburgh

Transcription

1 BHIVA Best of CROI Feedback Meetings London Birmingham North West England Cardiff Gateshead Edinburgh BHIVA Best of CROI Feedback Meetings 2010

2 ANTIRETROVIRAL TREATMENT STRATEGIES AND NEW DRUGS

3 A5202: Study Design HIV-1 RNA 1000 c/ml Any CD4+ count > 16 years of age ART-naïve 1857 N=1858 enrolled Arm A B TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD EFV QD EFV QD Randomized 1:1:1:1 Stratified by screening HIV-1 RNA (< or 100,000 c/ml) C TDF/FTC QD ABC/3TC Placebo QD ATV/r QD Enrolled Followed through Sept 2009, 96 wks after last pt enrolled D ABC/3TC QD TDF/FTC Placebo QD ATV/r QD

4 ABC/3TC vs. TDF/FTC Primary Virologic and Safety Endpoints (High Viral Load Stratum at DSMB Action) N=797; median (25 th, 75th) follow-up = 60 weeks (28, 84) Time to Virologic Failure Time to Safety Endpoint TDF/FTC (26 events) TDF/FTC (78 events) ABC/3TC (57 events) ABC/3TC (130 events) Log rank test p-value= HR (95% CI) 2.33 (1.46,3.72) Log rank test p-value< HR (95% CI) 1.89 (1.43,2.50) Sax PE, et al. NEJM 2009; 361:

5 Baseline Characteristics A5202: Overall EFV (n=465) ABC/3TC ATV/r (n=463) EFV (n=464) TDF/FTC ATV/r (n=465) All subjects (n=1857) Age (yrs), median Males (%) Race/Ethnicity (%) White non-hispanic Black non-hispanic Hispanic HIV RNA (log 10 c/ml), Median CD4 cells/mm 3, median History of AIDS (%) Genotype at screening (%) * HCV positive (%) * Required for those with recent infection, otherwise optional

6 Baseline Characteristics A5202: Overall EFV (n=465) ABC/3TC ATV/r (n=463) EFV (n=464) TDF/FTC ATV/r (n=465) All subjects (n=1857) Age (yrs), median Males (%) Race/Ethnicity (%) White non-hispanic Black non-hispanic Hispanic HIV RNA (log 10 c/ml), Median CD4 cells/mm 3, median History of AIDS (%) Genotype at screening (%) * HCV positive (%) * Required for those with recent infection, otherwise optional

7 EFV + TDF/FTC EFV + ABC/3TC ATV/r + TDF/FTC ATV/r + ABC/3TC A5202: Overall ATV/r vs. EFV Primary Virologic Endpoint ATV/r versus EFV with ABC/3TC: HR 1.13 (95% CI 0.82, 1.56) Prob. VF free at wk 96: 83.4 vs. 85.3%, diff -1.9% (95% CI -6.8, 2.6) TDF/FTC: HR 1.01 (95% CI 0.70, 1.46) Prob. VF free at wk 96: 89.0 vs. 89.8%, diff -0.8% (95% CI -4.9, 3.3) ABC/3TC + EFV (72 events) ABC/3TC + ATV/r (83 events) TDF/FTC + EFV (57 events) TDF/FTC + ATV/r (57 events)

8 EFV + TDF/FTC EFV + ABC/3TC ATV/r + TDF/FTC ATV/r + ABC/3TC A5202: Overall ATV/r vs. EFV Primary Safety Endpoint ATV/r versus EFV with ABC/3TC: HR 0.81 (95% CI 0.66, 1.00), p=0.05 TDF/FTC: HR 0.91 (95% CI 0.72, 1.15), p=0.44 ABC/3TC + EFV (187 events) ABC/3TC + ATV/r (170 events) TDF/FTC + EFV (147 events) TDF/FTC + ATV/r (141 events)

9 A5202: Overall ATV/r vs. EFV Primary Tolerability Endpoint ATV/r versus EFV with ABC/3TC: HR 0.69 (95% CI 0.55, 0.86), p= TDF/FTC: HR 0.84 (95% CI 0.66, 1.07), p=0.17 ABC/3TC + EFV (186 events) ABC/3TC + ATV/r (142 events) TDF/FTC + EFV (142 events) TDF/FTC + ATV/r (126 events) EFV + TDF/FTC EFV + ABC/3TC ATV/r + TDF/FTC ATV/r + ABC/3TC

10 A5202: Overall ITT Pre-Specified Targeted Events EFV (n=465) ATV/r (n=463) EFV (n=464) ATV/r (n=465) ABC/3TC TDF/FTC Cardiovascular, n (%) Vascular event * 29 (6) 2 (<1) 29 (6) 2 (<1) 35 (8) 6 (1) 20 (4) 1 (<1) Non-AIDS malignancies, n (%) 20 (4) 18 (4) 18 (4) 17 (4) Renal, n (%) 12 (3) 14 (3) 5 (1) 12 (3) Bone fractures, n (%) 22 (5) 16 (3) 21 (5) 21 (5) * Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease.

11 Percent A5202: Overall ITT Percent of Failures with Emergence of Major Resistance Mutations * ABC/3TC TDF/FTC p< p= p< p=0.046 p-values: ATV/r vs. EFV (amongst failures) A N Y A N Y A N Y A N Y M A J O R N N R T I N R T I P I M A J O R N N R T I N R T I P I M A J O R N N R T I N R T I P I M A J O R N N R T I N R T I P I Viral failures No baseline resistance N= ATV/r EFV ATV/r EFV * Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR

12 A5202: Overall: As-Treated ATV/r vs. EFV (wk 48) Median Change in Fasting Lipids (mg/dl) Cholesterol LDL HDL Triglyceride p<0.001 p<0.001 p<0.001 p=0.07 p-values: ATV/r vs. EFV p=0.002 p<0.001 p<0.001 p=0.26 EFV EFV EFV EFV EFV EFV EFV EFV ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ATV/r ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC N=

13 Change in Calculated Creatinine Clearance, (ml/min) A5202: Overall: As-Treated ATV/r vs. EFV Median Change in Creatinine Clearance Wk 48, p=0.17 Wk 96, p=0.33 Week 48 Week 96 Wk 48, p=0.001 Wk 96, p<0.001 p-values: ATV/r vs. EFV ATV/r ATV/r EFV EFV ABC/3TC TDF/FTC N=

14 A5202 Conclusions ATV/r Compared with EFV Similar time to virologic failure with both NRTIs * Longer time to safety event and to 3 rd drug modification with ABC/3TC Among virologic failures there was less resistance with both NRTIs Greater increase in CD4 with TDF/FTC Smaller increases in TC, LDL and HDL with both NRTIs Modest decline in creatinine clearance with TDF/FTC versus increase with ABC/3TC *Pre-specified equivalence boundary on HR not met, with observed week 96 event rate lower than projected (~15% vs. 32%). Difference and CIs for probability of being failure free at week 96 were within +10% criteria often used for defining equivalence (post-hoc).

15 Quad and GS-9350 Eligible Subjects Treatment-naïve HIV RNA 5,000 copies/ml CD4 cells >50 cells/mm 3 No Resistance to NRTIs NNRTIs PIs HBV- and HCV-negative 2:1 2:1 Quad + EFV/FTC/TDF placebo n = 48 EFV/FTC/TDF + Quad placebo n = 23 GS RTV placebo ATV + FTC/TDF n = 50 RTV + GS-9350 placebo ATV + FTC/TDF n = 29 Comparison EVG/GS-9350 vs. Efavirenz GS-9350 vs. RTV Randomization was stratified by HIV RNA ( or > 100,000 copies/ml) Primary Endpoint: Proportions with HIV RNA < 50 copies/ml at Week week trials

16 Baseline Characteristics Quad EFV/FTC/TDF GS-9350 RTV n=48 n=23 n=50 n=29 Age, mean years Male 92% 91% 94% 86% Race White 69% 78% 62% 55% Black 25% 22% 36% 28% HIV RNA Mean, log 10 copies/ml >100,000 copies/ml 23% 22% 24% 38% CD4 cells/mm 3, median AIDS 6% 4% 16% 10%

17 Percentage with HIV RNA <50 copies/ml Quad vs. EFV/FTC/TDF Primary Endpoint: Percentage with HIV RNA < 50 copies/ml (ITT M=F) % 83% Quad EFV/FTC/TDF Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) Week

18 Percentage with HIV RNA < 50 copies/ml GS-9350 vs. RTV with ATV + FTC/TDF Primary Endpoint: Percentage with HIV RNA < 50 copies/ml (ITT M=F) % 84% RTV GS Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) Week

19 Summary of Treatment-Emergent Adverse Events Quad EFV/FTC/TDF GS-9350 RTV n=48 n=23 n=50 n=29 Adverse Events related to Randomized Drug, Grades (35%) 13 (57%) 10 (20%) 7 (24%) Grade 3/4 Adverse Events 0 2 (9%) 2 (4%) 0 Adverse Events leading to discontinuation of study drug Serious Adverse Events (none related to study drugs) 0 1 (4%) 2 (4%) 1 (3%) 1 (2%) 1 (4%) 0 1 (3%)

20 Adverse Events >5% Related to Randomized Drug in Any Treatment Group Quad EFV/FTC/TDF GS-9350 RTV n=48 n=23 n=50 n=29 Abnormal Dreams, Nightmares 5 (10%) 8 (35%) 0 0 Dizziness 0 3 (13%) 0 0 Fatigue 4 (8%) 3 (13%) 1 (2%) 2 (7%) Somnolence 2 (4%) 2 (9%) 0 0 Headache 2 (4%) 2 (9%) 1 (2%) 0 Diarrhea 4 (8%) 1 (4%) 3 (6%) 3 (10%) Nausea 2 (4%) 1 (4%) 5 (10%) 1 (3%)

21 Treatment-Emergent Laboratory Abnormalities Grades 2-4 Occurring in >5% of Any Treatment Arm Quad EFV/FTC/TDF GS-9350 RTV n=48 n=23 n=50 n=29 Bilirubin, total /49 (82%) 25 (86%) Amylase 2 (4%) 2 (10%) 6 (12%) 2 (7%) Neutrophils, decreased 3 (7%) 2 (10%) 1 (2%) 1 (3%) Cholesterol*, total 4 (9%) 2 (10%) 3 (6%) 0 Proteinuria 1 (2%) 2 (10%) 2 (4%) 0 *Similar small median increases in cholesterol, LDL, HDL, triglycerides between arms in each study

22 Other Treatment-Emergent Laboratory Abnormalities Quad EFV/FTC/TDF GS-9350 RTV n=48 n=23 n=50 n=29 ALT Grades 2-4 AST Grades 2-4 Hypophosphatemia (All were Grade 1) Creatinine (All were Grade 1) (2%) 1 (3%) (3%) (2%) 1 (3%) 1 (2%) 0 6 (12%) 0

23 Cobicistat GS-9350

24 ODIN: study design ODIN (TMC114-C229) is a Phase IIIb, randomized, open-label study compares efficacy, safety and tolerability at Week 48 in treatmentexperienced adults with no DRV RAMs ARV-experienced patients, aged 18 years HIV-1 RNA >1000 copies/ml CD4 cell count >50 cells/mm 3 No DRV RAMs at screening* Stable HAART for 12 weeks 590 patients randomized Patients stratified by screening HIV-1 RNA ( 50,000, >50,000 copies/ml) Treatment phase (up to 48 weeks) DRV/r 800/100mg qd + OBR ( 2 NRTIs) (N=294) DRV/r 600/100mg bid + OBR ( 2 NRTIs) (N=296) *DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V; Individualized OBR included 2 N(t)RTIs based on ARV history and resistance testing ARV = antiretroviral; HAART = highly-active antiretroviral therapy; OBR = optimized background regimen; qd = once-daily; bid = twice-daily; RAMs = resistance-associated mutations

25 ODIN: baseline demographics and disease characteristics Baseline demographics Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) Female, n (%) 115 (39.1) 98 (33.1) Mean age, y (SE) 40.2 (0.53) 40.7 (0.55) Caucasian / Black / Hispanic, % 35 / 28 / / 24 / 20 Baseline disease characteristics Mean log 10 HIV-1 RNA (SE) 4.19 (0.05) 4.13 (0.05) Median CD4 cells/mm 3 (range) 219 ( ) 236 (44 864) Stratification factor at screening HIV-1 RNA 50,000 copies/ml, n (%) 222 (75.5) 224 (75.7) SE = standard error

26 ODIN: previous use of ARVs and optimized background therapy Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) Previous ARV experience*, n (%) NRTIs: (59.1) 164 (55.4) NNRTIs: (87.8) 258 (87.2) PIs: (45.9) 137 (46.3) PIs: 1 74 (25.2) 77 (26.0) PIs: 2 85 (28.9) 82 (27.7) Sensitivity to 8 PIs 248 (85.2) 247 (86.1) Optimized background therapy, n (%) Number of active NRTIs used 0 19 (6.6) 15 (5.3) 1 53 (18.3) 75 (26.4) (75.2) 194 (68.3) Median (range) DRV fold-change 0.5 ( ) 0.5 ( ) Median (range) mutations at baseline 1 PI RAMs 3 (0 13) 4 (0 14) Primary PI mutations 0 (0 5) 0 (0 4) *There were no restrictions on previous therapy with exception of previous or current use of enfuvirtide, tipranavir and/or DRV and current use of investigational drugs; Excluding ritonavir; Phenotypes were determined by Antivirogram PI = protease inhibitor 1. Johnson VA, et al. Top HIV Med 2008;16:

27 ODIN: previous use of ARVs and optimized background therapy Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) Previous ARV experience*, n (%) NRTIs: (59.1) 164 (55.4) NNRTIs: (87.8) 258 (87.2) PIs: (45.9) 137 (46.3) PIs: 1 74 (25.2) 77 (26.0) PIs: 2 85 (28.9) 82 (27.7) Sensitivity to 8 PIs 248 (85.2) 247 (86.1) Optimized background therapy, n (%) Number of active NRTIs used 0 19 (6.6) 15 (5.3) 1 53 (18.3) 75 (26.4) (75.2) 194 (68.3) Median (range) DRV fold-change 0.5 ( ) 0.5 ( ) Median (range) mutations at baseline 1 PI RAMs 3 (0 13) 4 (0 14) Primary PI mutations 0 (0 5) 0 (0 4) *There were no restrictions on previous therapy with exception of previous or current use of enfuvirtide, tipranavir and/or DRV and current use of investigational drugs; Excluding ritonavir; Phenotypes were determined by Antivirogram 1. Johnson VA, et al. Top HIV Med 2008;16: PI = protease inhibitor

28 Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) ODIN: viral load <50 copies/ml to Week 48 (ITT-TLOVR) % 70.9% DRV/r 800/100mg qd DRV/r 600/100mg bid 20 0 Difference in response qd vs bid: ITT: = 1.2% (95% CI = 6.1%, 8.5%) PP: = 0.9% (95% CI = 6.7%, 8.4%) Time (weeks) CI = confidence interval; PP = per protocol

29 Patients with HIV-1 RNA <50 copies/ml (% [95% CI]) ODIN: confirmed virologic response by screening HIV-1 RNA 100 DRV/r 800/100mg qd DRV/r 600/100mg bid N= ,000 >50,000 Screening HIV-1 RNA (copies/ml)

30 Median change in CD4 cell count from baseline (cells/mm 3 ) ODIN: median change in absolute CD4 cell count to Week 48 (LOCF) cells/mm 3 94 cells/mm DRV/r 800/100mg qd DRV/r 600/100mg bid Time (weeks) LOCF = last observation carried forward

31 C trough (ng/ml) ODIN: DRV plasma concentrations 100,000 10, DRV/r 800/100mg qd DRV/r 600/100mg bid N=280 N=278 (median, interquartile range, range) 1. Tibotec, data on file.

32 ODIN: summary of resistance Number of patients, n (%) Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) Virologic failures 65 (22.1) 54 (18.2) Never suppressed 54 (18.4) 43 (14.5) Rebounders 11 (3.7) 11 (3.7) Paired baseline/endpoint genotypes Developing Primary PI RAMs 1 1 (1.7) 0 Developing any PI RAMs 1 7 (11.7) 4 (9.5) Developing NRTI RAMs 1 4 (6.7) 3 (7.1) Paired baseline/endpoint phenotypes Loss of susceptibility to DRV 1 (1.7) 0 Loss of susceptibility to any PI 2 (3.4) 0 Loss of susceptibility to any NRTI in OBR 7 (11.9) 4 (9.8) Not significant; Also DRV RAMs 1. Johnson VA, et al. Top HIV Med 2008;16:

33 ODIN: summary of safety Parameter, n (%) Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) Mean exposure (weeks) Serious AEs 16 (5.4) 27 (9.1) Grade 3 4 AEs* 23 (7.8) 45 (15.2) 1 AE leading to permanent discontinuation 10 (3.4) 14 (4.7) Grade 2 4 AEs at least possibly related to DRV/r ( 2% incidence in either arm) Nausea 11 (3.7) 13 (4.4) Diarrhea 11 (3.7) 11 (3.7) Vomiting 7 (2.4) 9 (3.0) * Includes deaths (2 in qd group and 6 in bid group; none were considered by the investigator to be related to treatment with DRV/r)

34 ODIN: laboratory abnormalities Treatment-emergent grade 2 4 lipid and liver-related laboratory abnormalities ( 2% incidence), n (%)* Once-daily DRV/r 800/100mg (N=294) Twice-daily DRV/r 600/100mg (N=296) P value Triglycerides 15 (5.2) 31 (11.0) <0.014 Total cholesterol* 29 (10.1) 58 (20.6) < LDLc cholesterol* 28 (9.8) 47 (16.7) <0.019 ALT 5 (1.7) 10 (3.5) 0.20 AST 6 (2.1) 10 (3.5) 0.32 Non-graded lipid-related laboratory abnormalities, n (%) HDL below the lower normal limit 57 (19.9) 52 (18.4) 0.67 *Based on the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events 2004, which does not have a grade 1 classification for triglycerides and grade 4 for total cholesterol and LDL LDLc = low-density lipoprotein (calculated); ALT = alanine aminotransferase; AST = aspartate aminotransferase; HDL = high=density lipoprotein

35 ODIN: median fasting lipid concentrations DRV/r qd baseline DRV/r qd Week 48 DRV/r bid baseline DRV/r bid Week N= Triglycerides NCEP cut-off Left axis mg/dl; right axis mmol/l Total cholesterol LDL calculated HDL NCEP = National Cholesterol Education Program 0

36 VICTOR-E3 & 4: Phase 3 Trial Design VICTOR-E3 and 4 were identically designed, randomized, double-blind, placebo-controlled, 48-week multicenter Phase 3 studies Subjects were ART-experienced with: Documented resistance to 2 then available drug classes (NRTI, NNRTI, or PI) or ART experience of at least 6 months MITT population = 721 of 857 enrolled subjects R5 subjects enrolled based on Trofile Confirmed by Trofile ES at study conclusion (blinded) Treatmentexperienced R5-HIV only Total N =721 VCV 30 mg + OBT Placebo + OBT Week 24 Interim analysis Week 48 Final analysis Primary endpoint: % HIV RNA <50 copies/ml at 48 weeks

37 Baseline Characteristics (MITT) VICTOR-E3 VICTOR-E4 VCV Control VCV Control N Age, years (SE) 43 (0.6) 44 (0.9) 43 (0.6) 44 (0.8) White, n (%) 163 (65%) 85 (69%) 121 (52%) 67 (60%) Female, n (%) 85 (34%) 37 (30%) 66 (28%) 22 (20%) Mean baseline HIV RNA, log 10 (SE) 4.5 (0.1) 4.8 (0.1) 4.5 (0.1) 4.5 (0.1) Mean CD4 count, cells/mm 3 (SE) 246 (11.9) 221 (17.1) 273 (11.3) 287 (18.0) OSS 2, n (%) 106 (42%) 54 (44%) 70 (30%) 31 (28%) OSS 3, n (%) 141 (56%) 67 (54%) 152 (65%) 78 (70%) Raltegravir in OBT regimen, n (%) 95 (38%) 47 (38%) 59 (25%) 31 (28%) Darunavir in OBT regimen, n (%) 94 (37%) 51 (41%) 90 (38%) 46 (41%)

38 Disposition at 48 Weeks Pooled VICTOR-E3 & 4 (MITT) VCV (N=486) Control (N=235) Completed 48 weeks, n (%) 368 (75) 183 (78) Total discontinuations, n (%) 118 (24) 52 (22) Investigator-defined treatment failure 54 (46) 31 (60) Adverse Event 17 (14) 4 (8) Lost-to-follow-up 17 (14) 7 (13) Administrative 30 (25) 10 (19)

39 % HIV RNA <50 c/ml Virologic Response by OSS 100% VCV Control 80% 60% 70% 55% 61% 65% 40% 20% 0% n=176 2* n=85 n=293 3 n=145 Overall Sensitivity Score (No. of Active Drugs in Background) *Pre-specified subset; not adjusted for multiple analyses; Odds Ratio 1.9, P = 0.02.

40 % Patients Phenotypic Sensitivity Scores in Recent HIV Trials PSS = total number of phenotypically active drugs in background regimen Most vicriviroc trial participants had fully active background regimens In the MITT population, 461 (64%) of patients had 3 active drugs in OBT <1% 4% 29% Vicriviroc Phase 3 67% 12% 26% 25% Maraviroc Phase 3 37% 16% 31% 30% PSS =0 PSS =1 PSS =2 PSS 3 Raltegravir Phase 3 19% Schering-Plough Corp. Data on file; Fätkenheuer G, et al. NEJM 2008; Steigbigel RT, et al. NEJM 2008.

41 Resistance in Virologic Failures Frequency of OBT resistance similar in VCV and Control arms (~20%) Affected one or several drugs in OBT NRTI resistance was most commonly observed PI/r next most frequent Raltegravir resistance infrequent (~3%)

42 Common Adverse Events All Treated Subjects Adverse events in 5% of VCV-treated patients adjusted for total exposure VCV (n = 568) Years of exposure = 455 Control (n = 285) Years of exposure = 227 Number (%) Rate* Number (%) Rate* Any SAE 55 (10) (9) 11 Any TEAE 477 (84) (87) 109 Diarrhea 133 (23) (21) 27 Nausea 88 (15) (7) 8 Headache 69 (12) (15) 19 Nasopharyngitis 48 (8) (7) 9 Influenza 40 (7) 9 20 (7) 9 URTI 37 (7) 8 20 (7) 9 Vomiting 34 (6) 7 12 (4) 5 Insomnia 30 (5) 7 15 (5) 7 Back pain 27 (5) 6 17 (6) 8 Rash 27 (5) 6 12 (4) 5 Cough 26 (5) 6 18 (6) 8 *Per 100 patient years, all treated subjects.

43 Common Adverse Events All Treated Subjects Adverse events in 5% of VCV-treated patients adjusted for total exposure VCV (n = 568) Years of exposure = 455 Control (n = 285) Years of exposure = 227 Number (%) Rate* Number (%) Rate* Any SAE 55 (10) (9) 11 Any TEAE 477 (84) (87) 109 Diarrhea 133 (23) (21) 27 Nausea 88 (15) (7) 8 Headache 69 (12) (15) 19 Nasopharyngitis 48 (8) (7) 9 Influenza 40 (7) 9 20 (7) 9 URTI 37 (7) 8 20 (7) 9 Vomiting 34 (6) 7 12 (4) 5 Insomnia 30 (5) 7 15 (5) 7 Back pain 27 (5) 6 17 (6) 8 Rash 27 (5) 6 12 (4) 5 Cough 26 (5) 6 18 (6) 8 *Per 100 patient years, all treated subjects.

44 Events of Interest All Treated Subjects Population VCV n=568 Yrs of Exposure = 455 Number (%) Rate* Control n=285 Yrs of Exposure = 227 Number (%) Rate* Any adverse event 218 (38) (41) 52 Seizure ( 1) <1 Malignancy 7 (1) 2 4 (1) 2 Hepatocellular injury 57 (10) (9) 11 Dyslipidemia 33 (6) 7 21 (7) 9 URI 131 (23) (24) 30 HSV infection 37 (7) 8 23 (8) 10 Ischemic cardiovascular event 2 ( 1) <1 3 (1) 1 *Per 100 patient years, normalized by exposure; all treated subjects. 7 deaths in VCV arm; none in placebo

45 LEDGF/p75 integrase interaction inhibitors LEDGF/p75: co-factor of HIV integration Tethers integrase to chromatin X-ray structure demonstrates specific binding site 200, 000 small molecules screened. 4 molecules identified Christ et al. CROI 2010 Abstract 49

46 Desfarges et al., CROI 2010 Abstract 252

47 LEDGF/p75 integrase interaction inhibitors LEDGF/p75: co-factor of HIV integration Tethers integrase to chromatin X-ray structure demonstrates specific binding site 200, 000 small molecules screened. 4 molecules identified CXO4328 relatively selective No cross-resistance with raltegravir/elvitegravir Christ et al. CROI 2010 Abstract 49

48 TBR 652 (Tobira CCR5 antagonist; In vitro EC TAK 652) Plasma half life hours 10-days monotherapy Double-blind, placebo-controlled, dose ranging study 54 experienced patients, CCR5 tropic virus mg od Cohen et al., CROI 2010, Abstract 53

49 Martin et al., CROI 2010, Abstract 598

50 TBR log reduction with doses over 75mg No clear toxicity signal Also inhibits CCR2 (ligand MCP-1) Anti-inflammatory effect Cohen et al., CROI 2010, Abstract 53

51 Intensification studies Does adding an ARV agent to a suppressive regimen: Reduce HIV plasma RNA further (RAL, T-20) Reduce HIV DNA and 2-LTR circles (RAL) Increase plasma CD4 (T-20, MAR) Reduce GALT VL (or CD4) (MAR) Reduce the development of resistance (T-20)

52 Raltegravir intensification Study Design/size Duration of RAL Plasma RNA McMahon et al Single arm n=9 4 weeks No change Gandhi (A5244) RCT, cross-over n=53 12 weeks No change Hatano et al RCT n=30 24 weeks No change Buzon et al Randomised n=69 (45 added RAL) 48 weeks No change Yukl et al Single arm n=8 16 weeks No change Wiegand et al Single arm n=7 No change CD4 and CD8 activation No change in blood no change in blood or GALT Decrease blood CD8, increase in 2-LTR Decrease VL and immune activation in gut 2010 CROI: #100, #101, #279, #280

53 Intensification studies Does adding an ARV agent to a suppressive regimen: Reduce HIV plasma RNA further (RAL, T-20) NO Reduce HIV DNA and 2-LTR circles (RAL) NO Increase plasma CD4 (T-20, MAR) NO Reduce GALT VL or CD4 (MAR) NO Reduce the development of resistance (T-20)? Reduce immune activation Modest MESSAGE No CD4 or VL benefit: modest reduction in immune activation with MVC

54 ACTG 5217: SETPOINT Treatment in Primary Infection Early versus no treatment for early HIV infection PHI diagnosed by: Detuned assay Western blot 36 weeks ART Truvada + LPV/r Primary Endpoint: CD4 < 350 Commencing ART Endpoints at week 36: 0/39 vs 11/40 ART commencement at week 72: 4/39 vs 20/40 (p=0.005) Unusual methodologies VL measurements Method of analysis Results suggest a 16 week delay in the need for ART initiation but no effect thereafter SPARTAC results due 2011 Hogan et al; #134

55 Diagnosing Acute Infection CDC Acute HIV Infection Study (#1002) Comparison of different laboratory techniques in identifying acute HIV infection 99,111 specimens; 602 acute HIV Sensitivity of testing methods (vs RNA): 4 th generation: 88% 3 rd generation: 55-57% POCT: 22-38% Conclusion: If testing high-risk populations, need to use 4 th generation tests and careful use of POCT

56 BHIVA Best of CROI Feedback Meetings London Birmingham North West England Cardiff Gateshead Edinburgh BHIVA Best of CROI Feedback Meetings 2010