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When to START Antiretroviral Therapy?

When to START Antiretroviral Therapy?. Dr. José R Arribas HIV Unit. Non-IVDU. IVDU. Female. Male. Life expectancy of individuals on combination antiretroviral therapy in high-income countries. Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99.

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When to START Antiretroviral Therapy?

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  1. When to START Antiretroviral Therapy? Dr. José R Arribas HIV Unit

  2. Non-IVDU IVDU Female Male Life expectancy of individuals on combination antiretroviral therapy in high-income countries Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99

  3. Survival from age 25 years (Non HCV) Smoking? Lifestyle? Socioeconomic? HIV? Lohse N et al. Ann Intern Med. 2007;146:87-95.

  4. SMR in 2435 HIV-infected adults, ANRS CO8APROCO-COPILOTE, and ANRS CO3 AQUITAINE cohorts, 1997 to 2005. Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77

  5. SHOULD WE START HAART IN THIS PATIENT NOW? • 32 year old male • HIV negative: Sept/2000. HIV positive Dec/2000 • Nadir CD4 cell count: 453 • Current CD4 cell count: 479 • Current viral load: 16000 • No hepatitis coinfection. • HIV negative couple

  6. DEATH AIDS WAITING AHEAD (NO TREATMENT) 32 y/o male CD4 cell count: 479 Current viral load: 16000

  7. DEATH & AIDS. HAART and Survival Based on Initial CD4+ Cell Count Modeled data from ART Cohort Collaborative 10,855 patients included 934 progressed to AIDS or died IDUs censored from model Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART Initiating Rather than Deferring Haart at a CD4+ Count Between 351-500 Cells/mm3 is Associated with Improved Survival (74% Lower risk) Kitahata MM et al. ICAAC 2008. H-896b 0.14 101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3 0.12 0.10 0.08 Probability of AIDS or Death 0.06 0.04 0.02 0.00 3 4 5 1 2 0 Years Since Initiation of HAART Sterne J, et al. CROI 2006. Abstract 525.

  8. AIDS. Hazard Ratio from initiation of HAART to AIDS by CD4 cell count Similar data: ARTC Sterne J, et al. CROI 2006. Abstract 525. Jaen J, et al. JAIDS 2008;47:212–220

  9. PREDICTED 6-month risk of AIDS The NNT (Number Needed to Treat) is 203 This means that about one in every 203 patients will benefit from the treatment. 32 y/o male CD4 cell count: 479 Current viral load: 16000 BHIVA Guidelines 2008

  10. DEATH AIDS WAITING AHEAD (NO TREATMENT) 32 y/o male CD4 cell count: 479 Current viral load: 16000

  11. NON-AIDS EVENTS. SMART STUDY < 250 > 350 Of the 85 deaths that occurred in SMART, only 7 (8%) were due to opportunistic disease Adapted from SMART Study Group. N Engl J Med 2006;355:2283-96.

  12. DEATH AIDS NON-AIDS EVENTS CARDIOVASCULAR DISEASE RENAL DISEASE LIVER DISEASE CANCER WAITING AHEAD (NO TREATMENT) 32 y/o male CD4 cell count: 479 Current viral load: 16000

  13. 1.6 1.2 0.8 Rate / 100 person years 95% CI 0.4 0.0 Non-AIDS causes All causes 1.6 1.2 0.8 0.4 0.0 200 – 350 – > 500 349 499 200 – 350 – > 500 349 499 CD4 count (/mm3) NON-AIDS EVENTS. CD4+ Cell Count and risk of death CASCADE (ART-naïve) DAD Weber et al, Arch Intern Med 2006 Marin et al 4th IAS [WEPEB019]

  14. DEATH AIDS NON-AIDS EVENTS CANCER CARDIOVASCULAR OTHER “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION COST WAITING AHEAD (NO TREATMENT) 32 y/o male CD4 cell count: 479 Current viral load: 16000

  15. 0 48 96 144 192 240 288 336 0 1 2 3 4 5 “IRREVERSIBLE” IMMUNODEFICIENCY. CD4+ Count Response Based on Baseline CD4+ Count • Magnitude of CD4+ increase greatest if therapy started at low CD4+ counts, but greater likelihood of CD4+ count normalization with earlier therapy Johns Hopkins HIV Clinical Cohort ATHENA National Cohort 1000 1000 800 800 600 600 Mean CD4+ Count (cells/mm3) 400 400 200 200 0 0 Weeks From Starting HAART Years on HAART Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

  16. “IRREVERSIBLE” IMMUNODEFICIENCY.Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression Mocroft A, et al. Lancet 2007; 370: 407–13.

  17. HIV TRANSMISSION. HIV RNA level affects probability of HIV transmission 5 4.5 No GUD GUD 4 3.5 3 Probability of Transmission/1000 Coital Acts 2.5 2 1.5 1 0.5 0 <1700 1700- 12500- 38500+ GUD Log Viral Load (c/mL) GUD = genital ulcer disease. Gray R et alLancet 2001;357:1149-1153

  18. WAITING AHEAD (TREATMENT) 32 y/o male CD4 cell count: 479 Current viral load: 16000 • TOXICITY • RESISTANCE • Transmitted resistance • COST • QOL • DEATH • AIDS • NON-AIDS EVENTS • CANCER • CARDIOVASCULAR • OTHER • HIV TRANSMISSION • “IRREVERSIBLE” IMMUNODEFICIENCY • HIV TRANSMISSION

  19. TOXICITY.A5142: Lipoatrophy (> 20% loss Extremity Fat) 40 EFV LPV/r LPV/r + EFV P-values at Week 96 LPV/r+EFV vs LPV/r: 0.023 LPV/r+EFV vs EFV: <0.001 LPV/r vs EFV: 0.003 30 32% % Lipoatrophy (> 20% Loss) 20 21% 17% 10 10% 9% 7% 0 Weeks on Study 48 96 EFV 188 171 LPV/r 191 166 LPV/r + EFV 197 173 Haubrich R et al., 14th CROI, Los Angeles 2007, #38 ACTG A5142

  20. TOXICITY. HAART effect on CV risk driven by PIs RR adjusted by year of PI: 1.15 [1.062–1.25] 8 - RR adjusted by year of NNRTI: 0.94 [0.74–1.19] 7 - 6 - 5 - MIs per 1000 PYFU (95%CI) 4 - 3 - 2 - 1 - 0 - None <1 1-2 2-3 3-4 4-5 5-6 >6 D:A:D Friis-Møller N et al 13th CROI; 2006, #144

  21. TOXICITY. A5152s: VL Decrease Associated With Improved Endothelial Function HIV infection itself affected endothelial function Baseline FMD: 3.7% FMD improved during HAART No consistent correlations between changes in FMD and changes in any lipids or glycemic parameter Improvement in FMD significantly associated with decrease in HIV-1 RNA at Week 24 No relationship with baseline HIV-1 RNA 3.5 Week 4 Week 24 † 3.0 2.5 2.0 Median Change in FMD From Baseline (%) 1.5 * * * 1.0 0.5 0 Overall LPV/NRTI EFV/NRTI EFV/LPV *P < .01 compared with baseline. †P < .01 compared with baseline and within group. Torriani F, et al. Lipodystrophy Workshop 2007. Abstract O-18. Torriani F, et al. IAS 2007. Abstract WEAB302.

  22. RESISTANCE. Unadjusted and adjusted risk ratios of virological failure by year of starting cART Strategy A Unadjusted Adjusted 1 4.0 Adjusted 2 3.5 3.0 2.5 2.0 Risk ratio 1.5 1.0 0.5 1996 1997 1998 1999 2000 2001 2002 Year of starting CART 1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, pre-HAART VL and CD4, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd drug count and nucleoside combination. Lampe et al, Arch Intern Med 2006;166:521-528

  23. DEATH AIDS NON-AIDS EVENTS CANCER CARDIOVASCULAR OTHER “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION COST TOXICITY RESISTANCE Transmitted resistance COST QOL DEATH AIDS NON-AIDS EVENTS CANCER CARDIOVASCULAR OTHER HIV TRANSMISSION “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION 32 y/o male CD4 cell count: 479 Current viral load: 16000 NO TREATMENT TREATMENT

  24. PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular) & Toxicity & Transmission 32 y/o male CD4 cell count: 479 Current viral load: 16000 Framingham risk: 8% Hepatitis Coinfection: No

  25. NNT: ? NNH: ? PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular, Other) & Toxicity & Transmission 32 y/o male CD4 cell count: 479 Current viral load: 16000 Framingham risk: 8% Hepatitis Coinfection: No ? NNT (Prevent Transmission): ? NNH (Transmitted resistance): ?

  26. SMART SUBSTUDY (NAÏVE/OFF-HAART, > 350) Study halted early Virologic Suppression Strategy Continuous therapy (n = 249 not receiving ART at trial start) Patients with CD4+ cell count > 350 cells/mm³ who are antiretroviral naive (n = 249) or have not received ART for ≥ 6 mos (n = 228) (N = 477) Mean follow-up: 16 months Treatment Interruption Strategy Deferred therapy until CD4+ cell count < 250 cells/mm³; discontinue therapy when CD4+ cell count > 350 cells/mm³ (n = 228 not receiving ART at trial start)

  27. Opportunistic disease (fatal and non-fatal) Opportunistic disease and death Hazard Ratio = 4·40 (95%CI: 1·23-15·8) p=0·02 Hazard Ratio = 4·38 (95%CI: 1·45-13·.2) p=0·009 Deferred ART Immediate ART Cum. Probability (X100) Cum. Probability (X100) No. at Risk Months No. at Risk Months Deferred ART Deferred ART Def ART Immediate ART Immediate ART Imm ART Serious non-AIDS Composite endpoint Hazard Ratio = 7·05 (95% CI: 1·58-31·5) p=0·01 Hazard Ratio = 5·08 (95% CI: 1·91-13·5) p=0·001 Cum. Probability (X100) Cum. Probability (X100) No. at Risk Months No. at Risk Months Def ART Imm ART CLINICAL OUTCOMES SMART. The Journal of Infectious Diseases 2008; 197:1133– 44

  28. HIV-infected participants with CD4+ cell counts > 500 cells/mm3 Early ART Group Immediately initiate ART N=450 at 70 sites for pilot phase N=2,000 (est.) for definitive study Deferred ART Group Defer ART until CD4+ <350 cells/mm3 or symptoms develop N=450 at 70 sites for pilot phase N=2,000 (est.) for definitive study START: Design

  29. Composite Primary Endpoint(Time to first event) • AIDS* • Clinical events included in 1993 CDC case definition, plus additional conditions related to immunodeficiency (non-fatal esophageal candidiasis and herpes simplex are excluded) • Non-AIDS • Cardiovascular disease: MI, angioplasty, CABG, stroke • Chronic end-stage renal disease (ESRD): initiation of dialysis, renal transplantation • Decompensated cirrhosis • Non-AIDS defining cancers (basal and squamous cell skin cancers are not counted) • Death from any cause

  30. INDIVIDUALIZING FACTORS > 55 y/o ↑ Cardiovascular Risk Hepatitis Coinfection High Viral Load Rapid CD4 cell decline

  31. When to start antiretroviral treatment? • Current global consensus: < 350. This represents a prudent decision given the available evidence. • > 350?: • Precise estimates of the risk of Death/AIDS are available • Precise estimates of the risk non-AIDS (on/off HAART) events are not available • We do not know the exact individual risk/benefit ratio NNH/NNT. • We do not know the exact population risk/benefit ratio NNH/NNT. • A RCT might be a very important instrument but there are still questions about feasibility (enrolment, duration, duration of benefit, impact of toxicity, other)

  32. Dealing with uncertainty “The practice of medicine is an art, based on science. Medicine is a science of uncertainty and an art of probability”Sir William Osler

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