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Robert Murphy, M.D. Professor of Medicine Director, Center for Global Health

Current Treatment Practice and Future Treatment Options. Robert Murphy, M.D. Professor of Medicine Director, Center for Global Health Feinberg School of Medicine Northwestern University Chicago and Professeur Associé de Recherche Université Pierre et Marie Curie Paris.

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Robert Murphy, M.D. Professor of Medicine Director, Center for Global Health

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  1. Current Treatment Practice and Future Treatment Options Robert Murphy, M.D. Professor of Medicine Director, Center for Global Health Feinberg School of Medicine Northwestern University Chicago and Professeur Associé de Recherche Université Pierre et Marie Curie Paris

  2. Current Treatment Practice: Should there be two levels of guidelines? • The big questions remain: • When to start? When is too early? • What to use first? Does it really matter? • What alternatives do we have with the currently available drugs? New strategies? • Should we have 2 levels (rich and poor) of recommendations? No.

  3. When to Start HIV Therapy?Why Are Trials Hard? • Outcome of therapy started late is still “good” • Small expected differences require very large, very long period of study • Most potential subjects either: • Already in care • Don’t want care • Are not ideal trial participant • May have non-B clades (so what?) • May not be representative of “typical” chronic infection • Treatment paradigm may well change during trial (integrase as first line?) making results suspect • Treatment guidelines may anticipate “answer” and make trial impossible/unethical

  4. IAS-USA Guidelines 21 July 2010: When To Start IAS Guidelines Revised 21 July 2010, JAMA

  5. EACS Guidelines 2009: When to Start Therapy EACS Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe, Version 5, Nov 2009.

  6. DHHS Guidelines 12/2009: When To Start US DHHS Guidelines; Revised January 29, 2008. http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf

  7. What to Start: It all works in First Line…

  8. When to Start Therapy: then….. • Cost • Limited Second Line Options • Drug toxicity • Lipodystrophy • Neuropathy • Gastrointestinal • Resistance Delayed ART

  9. When to Start Therapy: now….. Preserve immune status Higher success rates Short term costs Less resistance Better tolerability Patient reluctance More treatment options Decrease HIV transmission CVD, neuro, renal, disease and age benefit Delayed ART Early ART

  10. Better Regimens: Proportion of patients experiencing failure of >2 distinct regimens has declined dramatically aRR=1.46 N ~ 30,000 REF aRR=0.82 aRR=0.51 aRR=0.54 NA-ACCORD, Clin Infect Dis 2009

  11. Prevalence of Specific Mutations Over a 7-Year Period: CNICS 58[53,63] 52[47,56] M184V 45[40,50] 45[41,49] ≥1 TAMs 38[33,42] 37[30,44] 30[26,34] 29[24,33] 37[32,41] Mean Prevalence, % [95% CI] K103N 26[20,32] 27[23,30] 16[12,19] 14[11,16] 16[11,22] 15[12,18] ≥1 ETR 12[7,16] 3[1,5] 5[2,8] 9[6,11] 7[5,9] K65R Aldous J, CROI 2010; 585.

  12. HIV Transmission Risk Serodiscordant Couples Initiating ARV HIV transmission risk 92% lower in African serodiscordant couples with HIV+ partner on ART vs couples with untreated partner 102 of 103 transmission occurred in couples with HIV+ partner not receiving ART Adjusted RR: 0.08 (95% CI: 0.002-0.57; P = .004) Adjusted for visit and CD4 count at initiation *Genetically linked HIV transmissions. Donnell D, et al. CROI 2010. Abstract 136.

  13. Lower CD4 Count and Detectable Viral Load Associated With Increased Risk of Death in D:A:D 10 5 1 0.5 0.1 CD4 and HIV RNA Status Overall AIDS Liver CVD Non-AIDS Malignancies Adjusted Rate Ratio (95% Cl) Per 100 <2.6 on >2.6 on <4 off 4-5 off >5 off CD4 VL (log c/mL) and ART Status Smith C and D:A:D Study Group. 16th CROI; 2009; Montreal. Abstract 145.

  14. Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start Magnitude of increase in CD4 count greatest if ART started at low CD4 counts, but greater likelihood of CD4 count normalization with earlier therapy 1000 1000 800 800 600 600 400 400 200 200 0 0 0 240 144 48 96 192 288 336 0 1 2 3 4 5 Johns Hopkins HIV Clinical Cohort1 ATHENA National Cohort2 Mean CD4 Count ≥500 350-500 >350 200-350 201-350 50-200 <200 <50 Years on ART Weeks from Starting ART 1Moore R, et al. Clin Infect Dis. 2007;44(3):441-446. 2Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

  15. Slower Immunologic Response and Greater Clinical Progression with Age > 50 *P < .0001 for younger than 50 years of age vs 50 years of age or older in all subgroups. Grabar S, et al. AIDS. 2004;18:2029-2038.

  16. NormalAging ART Toxicity Lifestyle Immune Dysfunction Slide #16 Non-AIDS events more common in HIV disease, even after adjustment for age, ART exposure and traditional risk factors Premature Aging

  17. Non-AIDS Events in Patients with Treated HIV Disease vs. Age-Matched HIV-Negative Controls Cardiovascular disease[1-4] Cancer (non-AIDS) Bone fractures/osteopenia [5,6] Left ventricular dysfunction Liver failure[7] Kidney failure Cognitive decline (?)[8] Frailty[9] 1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2. Hsue P, et al. Circulation. 2004;109:316-319. 3. Mary-Kraus M, et al. AIDS. 2003;17:2479-2486. 4. Grinspoon SK, et al. Circulation. 2008;118:198-210. 5. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8. McCutchan JA, et a. AIDS. 2007 ;21:1109-1117. 9. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286

  18. Immune Activation, HIV Infection and ART Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.

  19. Association Between Current CD4 Cell Count and Non-AIDS Complications Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.

  20. CD4 Count and Malignancy: French Hospital Database 52,278 pts (255,353 pt-yrs of follow-up) "Immunodeficiency increased the risk of all the cancers that we investigated… cART would be most beneficial if it restores or maintains CD4 count above 500 cells/μL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation." *Risk also increased with VL >100,000 vs. <100,000 Guiguet M, et al. Lancet Oncology 2009;

  21. CHARTER Study: Predictors of HIV-Associated Neurocognitive Disorders (HAND) Prospective observational study (N = 1525) Comprehensive neuropsychological and neuromedical testing conducted Risk of HAND associated with lower CD4 nadir, but not current CD4 count Remained significant after adjusting for other predictors: VL, age, sex, ethnicity, duration of infection 1.1 1 0.9 0.8 Odds Ratio for Cognitive Impairment 0.7 0.6 0.5 0.4 0.3 < 50 50-199 200-349 ≥ 350 CD4 Nadir Ellis R, et al. CROI 2010. Abstract 429.

  22. Cardiovascular Risk Brachial Artery Reactivity Testing 60 sec after cuff release 3 min after nitroglycerin Baseline 4.5 mm 5.0 mm, FMD=11% 5.3 mm, NTGMD=18%

  23. # ∆ FMD (%) * * * * Baseline FMD = 3.7% (2.0 – 5.5%) ACTG 5152s: Median Change in FMD Over Time *p≤0.01; #0.01<p≤0.05 compared to baseline, within group; **comparison between arms

  24. Cardiovascular Risk and CD4 Nadir CV risk strongly associated with arterial stiffness, as measured by: carotid-femoral pulse wave velocity (PWV) augmentation index (Aix@75) Nadir CD4 < 350 associated with 0.58 m/s increase in PWV (p=0.008) and 7.2% increase in Aix@75 (p=0.002). Adjusted for CV risk factors and HIV-related covariates (age, BP, HTN, DM, hypercholesterolemia, FMH, smoking, IDU, eGFR) No association with duration of ART or PI exposure Correlation between arterial stiffness and CD4 nadir Aix@75 r=-0.37 p=0.0009 PWV r=-0.25 p=0.03 Ho JE, et al. CROI 2010, San Francisco, Abstract 707

  25. NA-ACCORD: Early vs. Deferred ART Study controlled for factors that could affect decision to defer ART Adjustment for sex, age, and CD4 counts at baseline VL response similar in early vs. deferred arms Results similar when IDUs excluded Limitations: observational study with potential for unmeasured confounding Risk of Death With Deferral of ARTa aWithout inclusion of VL data. Adapted from Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.

  26. ART-CC: Prognosis based on CD4 count at initiation of ART ART Cohort Collaboration:15 cohorts from US and Europe (N = 24,444) 4.0 2.0 HR for AIDS or Death* 1.0 0.5 *Adjusted for lead-time and unobserved events. 0 500 400 300 100 200 CD4 Threshold Sterne J, et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only.

  27. Prospective Study in HaitiSevere et al. NEJM 15 July 2010 • Starting ART when CD4 <200 cells/uL vs 200-350 cells/uL • N = 810 • Deaths: 23 v 6 (CI 1.6,9.8; p=0.001) • New Tuberculosis: 36 v 18 (CI 1.2,3.6; p=0.01)

  28. Life Expectancy in HIV-infected Patients CD4 Nadir ART-CC1: Depending on when ART is started, life expectancy is 10-30 years less than that in uninfected patients AQUITAINE cohort2: Mortality same as that of general population in patients with CD4 >500 after 6th year of ART ATHENA cohort3: Modeled life expectancy for asymptomatic pts who remained naive and without AIDS at Wk 24 after Dx similar to age- and sex-matched uninfected controls: 52.7 vs 53.1 years 1. ART-Cohort Collaboration. Lancet.; 2. Lewden C, et al. J Acquir Immune DeficSyndr. 2007;46:72-7. 3. Van Sighem A, et al. CROI 2010. Abstract 526

  29. Future Treatment Options with Existing Drugs • Monotherapy following suppression • MONOI: effective, increase in body fat, future options preserved • PI/r plus raltegravir • As effective • Fewer adverse effects • Less lipoatrophy • What will it take to change the paradigm?

  30. Current Treatment Practice and Future Options: Recommendation for ART Low CD4 High VL Rapid CD4 decline Age Opportunistic diseases Pregnancy Cardiovascular risk HIVAN HBV/HCV coinfection Seronegative partner High-risk behavior Willingness to start Predicted non-adherence Reluctance to start

  31. Thank you! • Joel Gallant • Paul Volberding • Christine Katlama

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