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CROI 2010

CROI 2010 . Design: Quad- und GS-9350 Phase-2-Studien. Comparison. EVG/GS-9350/TDF/FTC + placebo n = 48. EVG/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.

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CROI 2010

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  1. CROI 2010

  2. Design: Quad- und GS-9350 Phase-2-Studien Comparison EVG/GS-9350/TDF/FTC + placebo n = 48 EVG/GS-9350 Eligible Subjects Treatment-naïve HIV RNA ≥5,000 copies/mL CD4 cells >50 cells/mm3 No Resistance to NRTIs NNRTIs PIs HBV- and HCV-negative • Randomization was stratified by HIV RNA (≤ or > 100,000 copies/mL) • Primary Endpoint: Proportions with HIV RNA < 50 copies/mL at Week 24 • 48-week trials 2:1 vs. EFV/FTC/TDF + placebo n = 23 Efavirenz GS-9350 + placebo ATV + FTC/TDF n = 50 GS-9350 2:1 vs. RTV + placebo ATV + FTC/TDF n = 29 RTV Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

  3. Baseline Characteristics Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

  4. Primary Endpoint:Percentage with HIV RNA < 50 copies/mL (ITT M=F) RTV vs. GS-9350 EVG/GS-9350/TDF/FTC vs. EFV/FTC/TDF 90% 86% 84% 83% % with HIV RNA <50copies/mL % with HIV RNA <50 copies/mL Week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%) Week 24 stratum-weighted difference -1.9% (95% CI: -18.4% to 14.7%) Week Week Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

  5. Adverse Events >5% Related to Randomized Drug in Any Treatment Group Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

  6. QUAD or GS-9350 Studies: Estimated GFR (Cockcroft-Gault) • No treatment discontinuations due to renal adverse events • Separate study in normal volunteers receiving GS-9350 or placebo for 7 days • Creat increase occurs in days, rapidly reversible, due to inhibition of tubular secretion by drug • No effect on GFR as measured by iohexol clearance • Effect similar to that seen with cimetidine or trimethoprim *Estimated GFR by Cockcroft-Gault Cohen C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 58LB.

  7. Design Victor E3 und 4 • 2 randomized, identical, placebo-controlled, double-blind, phase 3 trials • Subjects ART-experienced with either documented resistance to ≥ 2 available drug classes (NRTI, NNRTI, or PI) or ART experience of at least 6 months • Primary endpoint: % HIV RNA < 50 copies/mL at 48 weeks Treatment- Experienced R5-HIV only by Trofile ES (N=721) VCV 30 mg + OBT Placebo + OBT Week 48 Final analysis Week 24 Interim analysis Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB

  8. Victor E3 und 4: Baseline Charakteristika Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB

  9. Victor E3 und 4: Wirksamkeit (gepoolte Daten, MITT) N=85 n=176 n=293 n=145 Gathe J, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 54LB

  10. ACTG 5202 – Studiendesign EFV QD TDF/FTC QD TDF/FTC QD ABC/3TC Placebo QD ABC/3TC Placebo QD EFV QD ABC/3TC QD ABC/3TC QD ART-naïve(n=1857) TDF/FTC Placebo QD TDF/FTC Placebo QD ATV/r QD • 96 Wochen nach Einschluss letzter Patient • 2005-2007, kein HLA B* 5701-Test • 83% Männer, 40% Weiße • VL 4.7 log, CD4 230/µl, 40% Resistenztest • Vorhersage 32% VF zu Woche 96 ATV/r QD # 59LB Darr E et al

  11. A5202: Baseline Charakteristika * Required for those with recent infection, otherwise optional Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

  12. A5202: Zeit bis zum virologischen Versagen bei HIV-RNA >100.000 K/ml Wahrscheinlichkeit kein virologisches Versagen TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72) Kein Unterschied ATV/r und EFV Sax PE, et al. NEJM 2009;361:2230-2240.

  13. ACTG 5202: Wirksamkeit zu Woche 96 HIV RNA <100,000 K/ml Alle Patienten CD4-Veränderung/µl 250 251 252 221 P = 0.89 0.002 # 59LB Darr E et al

  14. ACTG 5202 • ATV/r > EFV – mehr NNRTI- und NRTI-Mutationen • ABC/3TC = TDF/FTC # 59LB Darr E et al

  15. ACTG 5202: ATV/r vs. EFVMittlere Veränderung Lipide und Kreatininclearance Median Change in Fasting Lipids (Week 48, mg/dL) 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 Change in Calculated Creatinine Clearance, (mL/min) Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

  16. ACTG 5202 • EFV > ATV/r – Erhöhung von TC, LDL, HDL • VL <100.000 ABC/3TC > TDF/FTC Erhöhung von TC, LDL, HDL # 59LB Darr E et al

  17. ACTG 5202 # 59LB Darr E et al

  18. ACTG 5224S • Substudie von ACTG 5202 • n = 269, 47% weiß • Knochen: • DEXA: Woche 0, 24, 48, 96, dann jährlich • Fettverteilung: • CT Abdomen: Woche 0 und 96 # 106LB McComsey G et al

  19. A5224s: Mean Percent Change in Lumbar Spine Bone Mineral Density (Week 192) NRTI Component: Primary Analysis NNRTI/PI Component: Secondary Analysis • Hip BMD: Significantly greater percent decline with TDF/FTC than ABC/3TC; not significant for NNRTI/PI • No significant difference in fracture rate between arms ABC/3TC TDF/FTC EFV ATV/r Lumbar Spine percent BMD change from week 0 to 192 P=0.004 P=0.035 McComsey, G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

  20. ACTG 5224s: Limb Fat Changes • No statistically significant differences incidence of 10% and >= 20% loss of limb fat between NRTI components and NNRTI/PI components (Fisher’s exact test) • Most study subjects gained limb fat; ATV/r increased limb/trunk fat more than EFV • Study confirms the very low rate of lipoatrophy with these regimens McComsey, G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.

  21. Design ODIN-Studie Treatment Phase (up to 48 weeks) • ARV-Experienced patients, aged ≥ 18 years • HIV-1 RNA > 1000 copies /mL • CD4 count > 50 cells /mm3 • No DRV Rams at screening* • Stable HAART for ≥ 12 weeks 590 patients randomized DRV/r 800/100mg QD + OBR (≥ 2 NRTIs )‡ (N=294) DRV/r 600/100mg + OBR (≥ 2 NRTIs )‡ (N=296) Patients Stratified by 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 OBR included 2 N(t)RTIs based on ARV history and resistance testing Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

  22. ODIN: Baseline Charakteristika Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

  23. ODIN: Wirksamkeit und Resistenz 72.1% 70.9% Difference in response qd vs bid ITT: 72.1-70.9=1.2% (95% CI=-6.1%, 8.5%) PP: 73.4-72.5=0.9% (95% CI=-6.7%, 8.4%) Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

  24. ODIN: Sicherheit • Once-daily DRV/r 800/100mg was effective and non-inferior to DRV/r 600/100mg bid in treatment-experienced HIV-1-infected patients with no DRV RAMs (and limited overall resistance) • The incidence of grade 2–4 lipid elevations with once-daily DRV/r 800/100mg was approximately half that of DRV/r 600/100mg bid Cahn P, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 57

  25. EuroSIDA Study: Risiko für chronische Nierenerkrankung • Analysis of patients with ≥3 creatinine measurements + body weight, 2004 • 6,842 patients with 21,482 person-years of follow-up • Definition of CKD (eGRF by Cockcroft-Gault) • If baseline eGFR ≥60 mL/min/1.73 m2, fall to <60 • If baseline eGFR <60 mL/min/1.73 m2, fall by 25% • 225 (3.3%) progressed to CKD Cumulative Exposure to ARVs and Risk of CKD • 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, 2010. Abst. 107LB.

  26. HOPS-Kohorte: Mehr Frakturen bei HIV-Infizierten Gender-adjusted rates of fracture among adults aged 25-54 years • Comparison of HOPS cohort (n=8456) vs National Hospital Discharge Survey and National Hospital Ambulatory Care Medical Survey • Adjusted for age and gender • Fractures: 276 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 = 0.01 NHAMCS-OPD P = 0.32 * Indirectly standarized using rtes from NHAMCS-OPD data Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.

  27. WIHS-Kohorte: Frakturen bei Frauen • Retrospective analysis of 1728 HIV+ and 663 HIV- • 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 Yin M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 130.

  28. Vitamin D in Swiss Cohort Study • Retrospective seasonal analysis of Vitamin D deficiency within Swiss cohort • Started ARV in: Fall (n=108); Spring (n=103) • 75% men; age = 37; White = 87%; CD4+ 227; BMI = 22.9 • ARVs: TDF – 17%; NNRTIs – 43%; PI -56% • Conclusions • Vitamin D deficiency is common, but seasonal • Blacks are at increased risk • NNRTI use a risk factor Vitamin D Deficiency is Not Influenced By ART Deficiency <30 nmol/L Target ≥75 nmol/L Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752.

  29. Vitamin D in Swiss Cohort Study

  30. Cancer Incidence in AIDS patients • Study of cancer risk in AIDS patients from 1980-2006 (n=372,364) • Predominantly male (79%), non-hispanic black (42%), MSM (42%) • Median age of 36 years at the onset of AIDS • Cancer risk in years 3 - 5 after AIDS onset increased for AIDS but also Non-AIDS defining cancers Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  31. Cancer Mortality in AIDS patients Population attributable risk among people with AIDS in the US Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

  32. Immunodeficiency and Non-AIDS Related Cancer • Predominantly male (90%), white (56%), MSM (75%), mean age of 40 years • Cancer related risk factors: • Smoking 39%, Overweight 39%, Alcohol abuse 19%, • HCV-infected 8%, HBV-infected 5% • Crude incidence rates and adjusted hazard ratios infection-related Non-AIDS defining cancers † cases per 100,000 person-years; ‡ Adjusted per age, sex, tobacco use, overweight/obese, alcohol/drug abuse, hepatitis B/C Silverberg et al. CROI 2010 Abstract 28

  33. Immunodeficiency and Non-AIDS related cancer • Crude incidence rates and adjusted hazard ratios non-infection-related Non-AIDS defining cancers † cases per 100,000 person-years; ‡ Adjusted per age, sex, tobacco use, overweight/obese, alcohol/drug abuse, hepatitis B/C Silverberg et al. CROI 2010 Abstract 28

  34. Effect of non-SVR on Risk of New ADCand Non–Liver-Related Death 0 1 10 • Crude • Adjusted 0 1 10 100 Berenguer, J. et al. Hepatology 2009;50:407-413; Berenguer, J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 167.

  35. Screening for Hepatocellular Carcinoma in HIV/HCV-Coinfected Patients • Retrospective study of 70 HIV-infected patients with HCV-related HCC (1992-2009) • Patients considered screened (n=39) if initially presented with an abnormal AFP level or liver imaging study, and not screened if they presented with symptoms • No significant differences between screened and non-screened patients regarding age, race/ethnicity, median HIV RNA level or median CD4+ cell count • Screened patients were more likely to present with earlier HCC stages and lower HCC staging score and to have longer time to mortality Cumulative Survival p=0.021 At Risk HCC Screen 39 10 5 3 1 No HCC Screen 31 0 Actuarial median survival: HCC screen 12.8 months No HCC screen 3.7 months Nunez, M, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 685.

  36. Life Expectancy ofHIV-Positive Patients Years of Life Remaining • Comparison of life expectancy of Athena cohort patients to general population • Enrolled those in ATHENA without AIDS Dx and did not start therapy for at least 24 weeks and excluded those with IDU • Included 4174 patients with 17,580 years of follow-up all diagnosed after 1998 • 3710 men; median CD4 at 24 weeks 480 cells/mm3 • Age at week 24, country of birth and stage B symptoms were associated with a higher risk of death • Expected life years remaining at age 25 was 53.1 (44.9-59.5) for general population and 52.7 for asymptomatic HIV+ patients • The modeled life expectancy of patient presenting at an older age and women were slightly lower that general population Age at time of death Years lived Remaining Life Years Age at 24 weeks (years) General Population Asymptomatic HIV+ Patients van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.

  37. Impact of Treatment Intensification on HIV Reservoirs and Immune Activation • RAL or T20 intensification in patients with suboptimal CD4 response  no effect1,2 • Increase in episomal cDNA following RAL intensification  suggest active replication persist in some HAART suppressed patients (~ 29%). Correlated with decrease in immune activation3 • MVC intensification of suppressive HAART  no effect on levels of immune activation and CD4 depletion in GALT4 • MVC intensification of suppressive HAART in patients with suboptimal CD4 response  no increase in CD4 but decrease in immune activation and improvement of markers of apoptosis5 1. Hatano H, et al. 17th CROI; San Francisco, CA, US; February 16-19, 2010. Abst. 101LB; 2. Joly V, et al. ibid. Abst. 282; 3. Buzon MJ, et al.ibid. Abst. 100LB; 4. Evering T, et al. ibid. Abst. 283; 5. Wilkin T, et al. ibid. Abst. 285.

  38. Early Initiation of Antiretroviral Therapy in HIV-Infected Individuals is Associated with Reduced Arterial Stiffness Significant determinants of PWV on Multivariate Analysis • Cross-sectional study assessing effect of earlier ART on CV risk • Enrolled 80 HIV-infected men on ARV Tx with undetectable HIV RNA • SCOPE study treated in the chronic phase of HIV infection (N = 65) • OPTIONS patients begin antiretroviral therapy within 6 months of HIV diagnosis. (N=15) • Median age 47 years, nadir CD4+ T cell count 180 cells/mm3 • Patients evaluated for CV risk by assessment of arterial stiffness by pulse wave analysis and carotid-femoral pulse wave velocity • Multivariable Predictors of Pulse wave velocity controlled for cardiovascular risk factors, HIV treatment duration and current CD4 Ho J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 707.

  39. Higher CD4 Nadir Associated with Less Neurocognitive Impairment Odds Ratio for Cognitive Impairment by CD4 Nadir 1.1 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 • Neurocognitive disorders assessed in the CHARTER prospective observational study • 1525 patients, 589 on ARV therapy • 603 had HAND (without a substantial confounder); 726 not impaired • Most with hand (n=428) were asymptomatic and only a few (n=27) had frank dementia Odds Ratio <50 50-199 200-349 ≥350 CD4 Nadir Odds Ratios for NP Impairment Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.

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