Sources of slides and information. roi/main.html. CME slide kit : Rush University Medical Center

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3 Sources of slides and information com/hiv conference/c roi/main.html CME slide kit : Rush University Medical Center

4 Modified from Rick Elion, MD Associate Professor, George Washington University School of Medicine, Washington, DC

5 1,378 Patients at 10 US Clinics followed From Median Peak CD4 was 900 progressively higher for 800 specific CD4 strata (p<0.001) 700 Multivariate analysis: Increased mortality with CD4 < (HR=4.6) and CD (HR=2.6) compared to 200 cells/mm Lower BL CD4 at initiation also 300 associated with increased risk 200 of death from non-aids-related causes Median CD4+ cell count versus years after HAART start by baseline CD4+ category < HAART start year 2 year 4 year 6 Palella F, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 983.

6 Proportion of CD4 350 cells/mm 3 at first presentation has increased from 34% to 47% (P 0.01) 01) Median CD4 on presentation has increased from 234 to 327 cells/mm 3 (P<0.01) NA-ACCORD ACCORD analysis (N=35,009) Still <50% of patients in the West Presented Late to Care Althoff K, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 982.

7 Washington DC has an estimated HIV seroprevalence 400 of 3% DOH expanded HIV testing to be included in 300 routine care with improved 250 clinical linkages From 2004 to 2006, HIV tests 200 increased from 19,000 to , Among newly diagnosed, median CD4 50 count increased 57% 0 ount at Presentati ion an CD4 C Medi CD4 at Initial Presentation HIV testing in routine care p< Year of Diagnosis i Castel A, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 34.

8 Multicenter t cohort study Odd R ti f C iti I i t b CD4 N di (CHARTER) of 1526 pts evaluating 40% had HAND (HIVassociated Neurocognitive Disorders 70% were asymptomatic only a few (n=27) had frank dementia Odd ds Ratio Odds Ratio for Cognitive Impairment by CD4 Nadir < CD4 Nadir High CD4 350 associated with a lower risk of HAND (multivariate analysis) Ellis R, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 429.

9 Period of declining new HIV diagnoses in BC coincident with increased HIV testing rates, increased uptake of antiretroviral therapy, and decrease in community viral load ( ) Decline in new HIV diagnoses despite increases in syphilis, gonorrhea, chlamydia Patients (n) 12,000 10, New HIV+ diagnoses (all) Censored at the time of death or move New HIV V+ Diagnos ses (n) HIV-1 RNA, copies/ < 500 ml ,000-49,999 50, Montaner J, et al. CROI Abstract 88LB. Reproduced with permission.

10 Evaluation of association between expansion of ART coverage, population level HIV viral load and new HIV diagnoses in British Columbia Expansion of ART access in associated with a significant decline in new HIV diagnoses After 2007, ~50% decrease in new HIV diagnoses among IDU occurred New HIV + Diagnoses (All) Active on HAART New HIV + Diagnoses (IDU) Montaner J, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 88LB.

11 Modified from Joseph Eron, MD Professor, University of North Carolina School of Medicine, Chapel Hill, NC And

12 ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV Stratified by HIV-1 RNA < or 100,000 copies/ml Wk 96 primary endpoint *Double blind. Open label. Antiretroviral-naive patients with HIV-1 RNA 1000 copies/ml and any CD4+ cell count (N = 1857) TDF/FTC* 300/200 mg QD +EFV 600 mg QD (n = 464) ABC/3TC* 600/300 mg QD + EFV 600 mg QD (n = 465) TDF/FTC* 300/200 QD + ATV/RTV 300/100 mg QD (n = 465) ABC/3TC* 600/300 mg QD + ATV/RTV 300/100 mg QD (n = 463) Daar E, et al. CROI Abstract 59LB.

13 bility of No Virologic Fa ailure (% %) Proba Probability of No Virologic Failure TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank test Hazard ratio, 2.33 (95% CI, ) Results similar between EFV and ATV/r arms Weeks since Randomization No. at Risk ABC- 3TC TDF-FTCFTC These results were not different by EFV vs. ATV/r arm Sax PE, et al. NEJM 2009;361:

14 Similar time to virologic failure with ATV/RTV vs EFV when combined with either ABC/3TC or TDF/FTC in overall population analysis With ABC/3TC, C, HR: 1.13 (95% CI: ) With TDF/FTC, HR: 1.01 (95% CI: ) ut (%) nts Withou c Failure ( Patien Virologi ATV/RTV EFV % without VF ABC/3TC TDF/FTC Daar E, et al. CROI Abstract 59LB.

15 nt Perce ABC/3TC 6565 TDF/FTC Viral failures No baseline resistance (N) 60 Any Major Mutation 50 NNRTI Mutation P< P< NRTI Mutation P= P= PI Mutation ATV/r EFV ATV/r EFV 23 Modified from CCO P-values: ATV/r vs. EFV (among failures) * 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 Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 59LB.

16 From %) in BMD F o Wk 96 (% Mean BL to Comparison of ABC/3TC vs Comparison of EFV vs TDF/FTC ATV/RTV ABC/3TC TDF/FTC EFV ATV/RTV P =.004 P =.025 P =.035 P =.59 0 n = Difference: 2.0% Difference: 1.5% From %) in BMD F o Wk 96 (% Mean BL to n = Difference : 1.5% Difference: 0.3% Lumbar Spine Hip Lumbar Spine Hip Initial loss in BMD in all arms stabilized after Wk 48 No significant differences in fracture rates between arms McComsey G, et al. CROI Abstract 106LB.

17 Can intensification ifi ti with a new class ARV improve CD4 counts? in viral suppressed patients with HAART for >48 wks but remaining suboptimal CD4 count Adding maraviroc Adding raltegavir

18 Intensification of Stable HAART in Pts With Suboptimal CD4+ Cell Counts ACTG 5256: Maraviroc added for 24 wks in 32 pts with HIV-1 RNA < 50 copies/ml for 48 wks on stable HAART but CD4+ cell count < 250 cells/mm 3[1] Maraviroc intensification not associated with clinically significant CD4+ gain Median CD4+ count increase at Wk 22/24: +12 cells/mm 3 (90% CI: 1-22) Decrease in CD4+/CD8+ activation and improvements in markers of apoptosis, but not correlated with change in CD4+ cell count Raltegravir intensification also not associated with significant CD4+ cell count increases in suppressed pts with low CD4+ cell counts [2] 1. Wilkin TJ, et al. CROI Abstract Hatano H, et al. CROI Abstract 101LB.

19 Modified from Calvin Cohen, MD Research Director, CRI New England Harvard Vanguard Medical Associates Boston MA

20 ODIN: Study Design Phase IIIb, randomized, open-label study Treatment phase (up to 48 weeks) 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 DRV/r 800/100mg qd + OBT (n=294) DRV/r 600/100mg bid + OBT stratified by (n=296) screening HIV-1 RNA ( 50,000, >50,000 copies/ml) * DRV RAMs include the following mutations: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V Individualized OBT included 2 N(t)RTIs based on ARV history and resistance testing Only restrictions on previous therapy: use of enfuvirtide, tipranavir, DRV, current use of investigational drugs ARV = antiretroviral; HAART = highly-active antiretroviral therapy; OBT = optimized background therapy; qd = once-daily; bid = twice-daily; RAMs = resistance-associated mutations Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, Abst. 57

21 ODIN: HIV-1 RNA < 50 copies/ml at Wk 48 Overall and by Screening HIV-1 RNA Pts With HIV-1 RNA < 50 copie es/ml (%) Difference in response, QD vs BID: ITT = 1.2% (95% CI: -6.1%, 8.5%) Wks QD DRV/RTV 800/100 mg BID DRV/RTV 600/100 mg Pts With HIV-1 RNA < 50 copie es/ml (%) n = ,000 > 50,000 Screening HIV-1 RNA (copies/ml) 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.

22 ODIN: Virologic Failure Not Statistically Different Between Arms Resistance Emergence in Pts QD DRV/RTV + BID DRV/RTV + With Virologic Failure and OBR OBR Paired Genotypes/Phenotypes Development of new RAMs,* n (%) Primary PI 1 (1.7) 0 Any PI 7 (11.7) 4 (9.5) Loss of susceptibility, n (%) Darunavir 1 (1.7) 0 Any PI 2 (3.4) 0 *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). Cahn P, et al. CROI Abstract 57.

23 ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID AEs,* % QD DRV/RTV BID DRV/RTV P Value + OBR + OBR (n = 294) (n = 296) Serious AEs Grade 2-4 treatment-related related lab abnormalities* Total cholesterol <.0007 LDL-C <.019 Ti Triglycerides id <.014 *No significant differences in grade 3/4 AEs, AEs leading to treatment discontinuation, GI AEs, ALT levels, or AST levels. Cahn P, et al. CROI Abstract 57.

24 Modified from Andrew Zolopa, MD Associate Professor, Stanford University School of Medicine Palo Alto, CA

25 % Virologic Failure *ASP detects specific mutations Sensitivity to 0.1% 41% 14% ASP+ ASP 9% 9% 32% 13% NVP LPV/r NVP Overall Baseline GT: no NNRTI R Boltz V, et al. 17th CROI; San Francisco CA USA; February 16-19, Abst. 154.

26 Report of HIV superinfection in MSM (M1 and M2) Source patient (M2) MDR HIV on partially suppressive LPV/r + ABC/3TC regimen Superinfected patient (M1) HIV RNA<50 c/ml on ABC/AZT/3TC Sudden increase in HIV RNA to >200 c/ml with further rebound Rebound associated with 3 class resistance that matched M1 Phylogenetically related viruses found in M1 and M2 M1 HIV displaced by M2 HIV Resistance mutations to ART present in M1 ( ) and M2 (2008) HIV-1 genotypic analyses RTI Mutations 41L 74I 75M 75T 98G 103N 108I 115F/Y 184V 215Y 318F 399D M1 X X X X X X N X X X X M2 X X X X X X X X X X Pl Mutations 10V 13V 20R 32I 33I 46I 47V 50V 71I 77I 82A 89V 90M 93L M1 X X X X X X X X X X N X X X M2 X X X X X X X X X X X X X Castro E, et al. 17th CROI; San Francisco CA USA; February 16-19, Abst. 480.

27 Modified from Paul Sax, MD Associate Professor, Harvard Medical School Boston, MA

28 ABC/3TC Median Change in Fasting Lipids (mg/dl) TC LDL HDL TG ATV/r EFV p-value <0.001 <0.001 < TDF/FTC ATV/r EFV p-value < < In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r Daar E, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 59LB.

29 Change in Calculated Creatinine Clearance (ml/min) Week 48 Week 96 ABC/3TC ATV/r EFV p-value TDF/FTC ATV/r EFV p-value <0.001 Daar E, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 59LB.

30 TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD Enrolled in Substudy EFV QD N=69 EFV QD N=70 EFV vs. ATV/r TDF/FTC vs. ABC/3TC EFV N=139 TDF/FTC N=139 TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD ATV/r QD N=65 ABC/3TC N=135 ATV/r N=130 ATV/r QD N=65 Study Evaluations: - DXA at 0, 24, 48, 96 weeks, then yearly - CT abdomen at 0 and 96 weeks - Serum lipids and plasma Primary endpoints (TDF/FTC vs. ABC/3TC): 1) Percent change in hip and lumbar spine BMD 2) 10% loss of limb fat Secondary endpoints: 1) bone and fat loss between EFV and ATV/r 2) on-study fractures McComsey, G, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 106LB.

31 P=0.004 D percent eek 0 spine BMD ge from we Lumbar s chang NNRTI/PI Component Secondary Analysis P=0.035 ATV/r EFV Visit from randomization (week) * linear regression No significant interaction of NRTI and NNRTI/PI components (P=0.63) McComsey G, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 106LB.

32 Randomized, double-blind blind study comparing RAL vs EFV, both with TDF/FTC Week 96 lipids (all pts, n=563) EFV increased TC, HDL- C, LDL-C, TG, and glucose significantly more than RAL No significant difference in total/hdl chol ratio Dexa substudy (n=111) Overall, limb fat increased over time By week 96, 3/37 pts on RAL, 2/38 on EFV had >20% loss of limb fat Lipid Changes p <0.001 * P =0.025 * Mean Percent Change in Appendicular Fat DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 720.

33 Modified from Ian Frank, MD Professor of Medicine Director, Clinical-Therapeutics Program University of Pennsylvania Center for AIDS Research Philadelphia, PA

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35 Methods: Time from D:A:D enrollment to first MI by time-updated TG level Adjustments for associations of independence from other CAD risks Subjects (n = 30,703): Age 39; White 54%; Current smoker 37%; CD4+ 407; HIV RNA BLQ 33% 580 MIs over 178,835 PY After adjustments for other CVD risks, doubling n = 30,703 of TG associated with an 11% increased risk for MI Incidence of MI according to TG group PY = Patient-Years Worm S, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 127.

36 N= 6,842 with 33 creatinine measurements + body weight (2004) : with 21,482 person-years of follow-up Definition of CKD (egfr by Cockcroft-Gault) If baseline egfr 60 ml/min/1.73 m 2, fall to <60 If baseline egfr <60 ml/min/1.73 m 2, fall by 25% 225 (3.3%) progressed to CKD Cumulative Exposure to ARVs and Risk of CKD ARV Multivariable IRR/year 95% CI P-value Tenofovir < Indinavir < Atazanavir Lopinavir/r Risk factors for CKD on TDF: age, HTN, HCV, lower egfr, lower CD4+ count Kirk O, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 107LB.

37 Comparison of HOPS cohort Gender-adjusted rates of fracture (n=8,456) vs National Hospital among adults aged years Discharge Survey and National Hospital Ambulatory Medical Care Survey (NHAMCS) Adjusted for age and gender HOPS: 276 Fractures during median 4.8 yrs follow-up Risk factors for fractures Age >47 Nadir CD4+ count <200 HCV co-infection Diabetes Substance use Conclusion: Fracture rates are higher in HIV infected population and rate is increasing with age HOPS P value for trend = 0.01 P value for trend = 0.32 NHAMCS- OPD Dao C, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 128.

38 Retrospective analysis of 1728 HIV+ and 663 HIV- individuals Fractures at hip, spine, wrist or other site Ever or within past 6 months Demographics (HIV+) 56% black, median age = 40, BMI = 28 Medical History (HIV+) Smoking 45%, Vitamin D supplements 42%, Menopause 20%, HCV+ 25% CD4+ count = 482 On ARVs 66%; Median years ART 5 +/- 10 No. Incident Fracture (%) HIV + HIV - Fracture/ 100 py No. Incident Fracture (%) Fracture/ 100 py P-value Any Site 148 (9%) (7%) Spine 15 (1%) (1%) Hip 15 (1%) (1%) Wrist 25 (1%) (1%) Other 105 (6%) (4%) Yin M, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 130.

39 Modified from Jürgen Rockstroh, MD Professor, University of Bonn Bonn, Germany

40 Population attributable risk among people with AIDS in the US Cumulativ ve Incide ence (%) AIDS Defining Cancer NonAIDS Defining Cancer Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

41 VA-Cohort (3,707 HIVpositive patients) Predominantly male (98%), 30 white (43%) Median age 47 years Lung cancer risk factors Smoking and drug abuse more often among HIV+ Similar rates of COPD After adjustment for smoking, risk of lung cancer higher in HIV+ patients Cases per 10,000 pt y yrs cases per 10,000 pt-yrs HIV+ 15 cases per 10,000 pt-yrs HIV IRR for lung 1.5 (95% CI: ) Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 30.

42 Modified from Edwin DeJesus, MD, FACP Medical Director, Orlando Immunology Center Orlando, FL

43 urban poor population In comparison to other commonly prescribed regimens, EFV/TDF/FTC exhibited higher rates of adherence and virologic suppression Virological i l suppression was better with EFV/TDF/FTC even when comparing patients with lower adherences rates Bangsberg D, et al. 17th CROI; San Francisco, CA; February 16 19, Abst. 510.

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45 New CCR5-inhibitor Vicriviroc (Merck ) Phase III Results

46 Wk 48 Treatmentexperienced patients infected with CCR5-tropic HIV-1 only (N = 721*) Vicriviroc 30 mg QD + OBR (VICTOR-E3: n = 252; VICTOR-E4: n = 234) Placebo + OBR (VICTOR-E3: n = 123; VICTOR-E4: n = 112) *Modified ITT population includes patients with CCR5-only tropism at baseline, confirmed retrospectively using enhanced sensitivity phenotypic tropism assay. OBR selected by investigator: must contain 2 fully active drugs; must include ritonavir-boosted PI; etravirine only permitted NNRTI; raltegravir and darunavir permitted. Gathe J, et al. CROI Abstract 54LB.

47 % with viral loa ad <50 c/ml Vicriviroc Placebo 70* *p= CD4+ count increased 138±7.33 with vicriviroc vs 29 ± 9.4 cells/mm 3 with placebo 0 Overall OSS 3 OSS 2 OSS = overall N= 486; 235 N= 293; 65 N= 176; 85 Gathe J, et al. CROI Abstract 54LB. sensitivity score

48 Lack of incremental benefit from vicriviroc i i may reflect high underlying activity of OBR Pts, % Vicriviroc Phase III [1] Maraviroc Phase III [2] Raltegravir Phase III [3] PSS = 0 < PSS = PSS = PSS = Gathe J, et al. CROI Abstract 54LB. 2. Fätkenheuer G, et al. N Engl J Med. 2008;359: Steigbigel RT, et al. N Engl J Med. 2008;359:

49 But will investigate as first-line Rx

50 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 EVG/GS-9350/TDF/FTC + placebo n=48 EFV/TDF/FTC + placebo n=23 GS placebo ATV + FTC/TDF n=50 RTV + placebo ATV + FTC/TDF n=29 Randomization stratified by HIV RNA ( or >100,000 copies/ml) Primary Endpoint: Proportions with HIV RNA <50 copies/ml at Week week trials Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 58LB.

51 with pies/ml ercentage w NA <50 cop Pe HIV RN EVG/GS-9350 vs. EFV Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) Week 90% 83% EVG/GS-9350/TDF/FTC EFV/FTC/TDF with pies/ml ercentage w RNA <50 co P HIV R RTV vs. GS-9350 Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) Week 86% 84% RTV + ATV + TDF/FTC GS ATV + TDF/FTC Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 58LB.

52 under development by Tobira Potent Oral CCR5 and CCR2 receptor antagonist In vitro protein-adjusted EC50=0.29 nm for R5 Neither a CYP inducer nor inhibitor Additive / synergistic activity with other ART classes in vitro Oral bioavailability y( (current formulation) enhanced by food Once daily dosing (Plasma T ½=35-40 hours) Study Design: Ten day monotherapy, R5-tropic pts CCR2 receptors are associated with, and currently being studied in several inflammation-associated associated diseases (atherosclerosis, rheumatoid arthritis, insulin resistance) Thus far no significant safety signals are identified with CCR2 antagonists Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, Abst. 53

53 Median VL Response Nadir Viral load Response 10 day dosing Note: CCR2 inhibition observed using MCP-1 level increases Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, Abst. 53

54 TBR-652: Summary of Adverse Events TBR-652 Dose Cohort Placebo 25 mg (n=9) 50 mg (n=7) 75 mg (n=9) 100 mg (n=10) 150 mg (n=9) (n=10) Any SAE Any AE Diarrhea Abdominal discomfort Fatigue Nausea Pyrexia Headache * AEs in 2 patients or more per cohort judged at least possibly related to study drug. Cohen C, et al. 17th CROI; San Francisco CA USA; February 16-19, Abst. 53