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  1. Initiation of antiretroviral treatment Dr. José R Arribas Prof. Christine Katlama

  2. Viral suppression > 90% • Immune restoration • Better ARV drugs • Simplified treatment • Increased survival • Transmission reduced HIV : a success story of research

  3. Pathogenesis New paradigm Inflammation induced by HIV replication is highly deleterious

  4. 15 DC 10 VS % cumulated events 5 p < 0,0001 0 DC VS 0 24952512 4 1839 1848 8 1441 1434 16 915 931 20 733 754 24 569 601 28 449 490 36 297 310 40 178 184 44 34 41 12 1112 1122 32 375 398 Mois depuis la randomisation Nb patients 2005 The SMART yearsHIV replication is associated to increased mortality and morbidity El-Sadr W.,NEJM 2006,

  5. SMART : Risque de décès associé à une augmentation des marqueurs de l’inflammmation et de la coagulation Marker Un-adjusted Adjusted OR (4th/1st) P-Value OR (4th/1st) P-Value Hs-CRP 2.0 0.05 2.8 0.03 Amyloid A 2.2 0.07 2.6 0.09 Amyloid P 0.7 0.39 1.1 0.84 IL-6 8.3 <0.0001 11.8 <0.0001 D-Dimer 12.4 <0.0001 26.5 <0.0001 F1.2 1.0 0.92 1.2 0.66 *Adjusted for age, race, ART, VL, BMI, Cholesterol, Smoking, Hepatitis, Statins, BP med’s Kuller LH, et al. PLoS Med. 2008;5:e203.doi;10.1371/journal.pmed.0050203

  6. Increase in risk of hypertension , diabetes and osteoporosis according to age in HIV-infected patients Hypertension Diabetes G Guaraldi Poster CROI 2010#727 Cardio-vascular event Osteoporosis 748 HIV+ patients fooled in Modena from 2002 to 2008 et 1219 contrôls paired on age and gender

  7. HIV- HIV+ INCIDENCE Non HIV related Comorbidities 10-15 ans AGE

  8. Pathogenesis of HIV HIV Immune activation Inflammation Immune deficit Cardiovascular risk Bone Cognitive disorders HBV/HCV Cancers Immune deficit Accelerated aging Cancers AIDS Cancers HIV is deleterious by immune suppression and activation

  9. HIV : a unique killer No one good reason to let it replicate ! CD4+ Plasma HIV RNA Virémie cellulaire Années

  10. When to Start ART ? • Much better ARV drugs - Potency - Simplicity Tolerability • Larger number of options • Deleterious effect of HIV • Reduction HIV transmission Later • Long term ART Complications • Cost • Uncertainty ? EARLY Less and less arguments not to start ART early

  11. International Guidelines * XTC= 3TC or FTC

  12. When to start antiretroviral therapy ? In case of opportunistic Infections (including TB) when do we start?

  13. ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs Stratified by CD4+ cell count < or  50 cells/mm3, PCP, BI, or other OI Immediate Antiretroviral TherapyInitiation within 48 hrs of randomization and within 14 days of starting OI treatment(n = 141) HIV-infected patients receiving treatment for presumed or confirmed acute OI/BI* (N = 282) 48 wks Deferred Antiretroviral TherapyInitiation between Wks 4 and 32(n = 141) 48 wks • 3-category primary endpoint • AIDS progression/death • HIV-1 RNA < 50 copies/mL; no progression • HIV-1 RNA ≥ 50 copies/mL; no progression *Patients with TB excluded. Only OIs with effective antimicrobial therapy permitted: PCP, BIs, cryptococcal disease, MAC, toxoplasmosis Zolopa AR, et al. PLoS One. 2009;4:e5575.

  14. ACTG A5164: Improved Outcomes With Immediate ART During Acute OI 92% treatment naive Median baseline CD4+ cell count 29 cells/mm3; HIV-1 RNA 5.07 log10 copies/mL Median duration from start of OI treatment to initiation of HAART Immediate group: 12 days Deferred group : 45 days Safety and incidence of IRIS similar between groups 3-category primary endpoint similar between groups at Wk 48 100 80 60 Patients Progressing to AIDS or Death at Wk 48 (%) P = .035 40 24.1 20 14.2 0 Immediate Deferred • However, secondary endpoint of AIDS progression/death improved with immediate antiretroviral therapy Zolopa AR, et al. PLoS One. 2009;4:e5575.

  15. CAMELIA (CAMbodian Early vs. Late Introduction of ART) Impact on Survival of Early vs. Late Initiation of HAART In HIV-infected Adults with Newly Diagnosed Tuberculosis to compare the impact upon mortality of early (2 weeks) vs. late (8 weeks) HAART initiation after TB treatment onset in treatment-naïve adults with newly diagnosed acid-fast bacilli (AFB) positive TB and CD4+ cell count < 200 cells/mm3. Patients received standard 6-month TB treatment plus stavudine, lamivudine and efavirenz and were followed through 50 weeks after the last patient was enrolled. . 661 patients (early, n=332; late, n=329) were enrolled. CD4+ cell count 25 cells/mm3and viral load 5.64 log copies/ml Kaplan-Meier Survival Estimates 1.00 Probability of Survival 0.75 0.50 P=0.042 0.25 0.00 0 50 100 150 200 Weeks After Randomization Late Early Blanc F, et al. 18th IAC; Vienna, July 18-23, 2010; Abst. THLBB106.

  16. CIPRAHT001: Randomized Trial of When to Start ART in Haiti Randomized clinical endpoint study of when to start therapy Early Treatment (Immediate ZDV/3TC + EFV) • Treatment-naive • No hx AIDS-defining illness • CD4 200-350(n=816) Primary endpoint: Survival Standard Treatment(Delay until CD4+ <200 or AIDS May 2009: DSMB review stopped study due to excess deaths in Defer Treatment arm Severe P, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1230c.

  17. CIPRAHT001: Clinical Endpoints and Additional Data Infectious causes of death Early: 1 (gastroenteritis) Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis) More toxicity from ART (especially anemia) and intensive need for lab f/u for those who deferred Investigators currently working with Ministry of Health to change start ART guidelines to 350 cells/mm3 Clinical Endpoints Severe P, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1230c.

  18. When to start antiretroviral therapy ?

  19. Randomized Trial We do not have this RCT Randomized clinical endpoint study of when to start therapy Early Treatment (Immediate HAART) • Treatment-naive • No hx AIDS-defining illness • CD4 350-500 Primary endpoint: Survival Standard Treatment (Delay until CD4+ <350 or AIDS

  20. ART CC The Lancet, Early Online Publication, 9 April 2009 doi:10.1016/S0140-6736(09)60612-7

  21. NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART Parameter Associated With Risk of Death Relative Hazard (95% CI) P Value Deferral of HAART until < 350 cells/mm3 (vs starting at 350-500 cells/mm3) < .001 1.7 Female sex 1.1 .290 Older age (per 10 yrs) 1.6 < .001 BL CD4+ cell count (per 100 cells/mm3 increase) 0.9 .083 0.1 1.0 2.5 • Increased relative hazard of death with deferral of HAART remained unchanged when adjusted for IDU or for HCV coinfection, which were both independent predictors of mortality Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b.

  22. CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds (351 & 500) significantly improved survival, as compared with deferred therapy. INTERPRETATION Our results suggest that 350 cells per μL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment The Lancet, Early Online Publication, 9 April 2009 doi:10.1016/S0140-6736(09)60612-7 N Engl J Med 2009;360. 10.1056/NEJMoa0807252

  23. When to start antiretroviral therapy ? • Treatment recommended if • hepatitis C co-infection, • HBV, • HIVAN • VL>105 c/ml and/or CD4 decline >50-100/mm3/year or age >50 or, pregnancy, • high cardiovascular risk, malignancy.

  24. When to start antiretroviral therapy ?

  25. Patients HIV+ with CD4 >500 cp/ml Early Therapy Start cART immediately n=600 in the initial phasen=1500 (estimation) in the final phase Differed therapy Start cART when CD4 <350 cells/µL or symptoms n=600 in the initial phasen=1500 in the final phase The START studyWhen to start ART therapy? Gordin et al. IAS 2007, MOSY205 oral presentation

  26. START : 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

  27. Late Early < 200 > 500 350 200 High viral load Any viral load CD4 New paradigm about HIV therapy Early treatment leads to: - Better control of HIV replication - Better quantitative and qualitative immune recovery - Less potential for resistance development - Decrease viral reservoir - Less immune activation and inflammation - Clinical benefit: HIV disease - Reduce interindividual transmission

  28. Benefits of early treatmentBénéfices Potentiels d’un Traitement Précoce Early Suppression of viral replication Preservation of immune function Decrease activation and inflammation Reduction of HIV diseases and comorbidities Decrease/interrupt viral transmission ; more confortable sexuality Improve quality of life Potential for a a light suppressive maintenance therapy

  29. Earlier treatment regardless of CD4 count

  30. ARTs: 2010 Combivir1,2, Trizivir1,2,3, Kivexa2,3, Truvada4,5, Atripla4,5,6

  31. Weighing the Options: Considerations for First-line Therapy

  32. International guidelines * XTC= 3TC or FTC

  33. What to start with ?

  34. ACTG A5202 : ABC/3TC versus TDF/FTC, combined to EFV versus ATV/r in naive HIV patients Double blind Open TDF/FTC qd + Placebo ABC/3TC qd A + EFV qd ABC/3TC qd + Placebo TDF/FTC qd 1 857 naive patients VL ≥ 1000 c/ml PNo restriction on CD4 RandomiZation 1:1:1:1 Stratified on VL < ou > 100 000 c/ml B + EFV qd TDF/FTC qd + Placebo ABC/3TC qd C + ATV/r qd ABC/3TC qd + Placebo TDF/FTC qd D + ATV/r qd Follow-up until last patient Week 96 Daar E, CROI 2010, Abs. 59LB

  35. ACTG 5202: Virological efficacy with ABC/3TC vs TDF/FTC In pts with screening VL < 100,000 c/mL Similar time to virologic failure with ABC/3TC vs TDF/FTC regardless of ATV/RTV or EFV With ATV/RTV, HR: 1.26 (0.76-2.05) With EFV, HR: 1.23; (0.77-1.96) In pts with screening VL ≥ 100,000 c/mL Shorter time to VF with ABC/3TC vs. TDF/FTC with either EFV or ATV/RTV With EFV, HR: 2.22 (1.19-4.14) With ATV/RTV, HR: 2.46 (1.20-5.05) Absence of VF in patients at 96 Wks for Pts with Screening VL < 100,000 copies/mL ABC/3TC TDF/FTC 100 90.3 89.2 88.3 87.4 80 60 Patients Without Virologic Failure (%) 40 20 0 ATV/RTV EFV Daar E, et al. CROI 2010. Abstract 59LB.

  36. ACTG 5202: Efficacité virologique ATV/r vs EFV 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, HR: 1.13 (95% CI: 0.82-1.56) With TDF/FTC, HR: 1.01 (95% CI: 0.70-1.46) ATV/RTV EFV 100 89.8 89.0 85.3 83.4 80 60 Patients Without Virologic Failure (%) 40 20 0 ABC/3TC TDF/FTC No VF at W96 Daar E, et al. CROI 2010. Abstract 59LB.

  37. PRIMARY RESISTANCE Canada ~8.5%1 UK: ~181† USA: ~10%1 France: ~123‡ Spain: ~9.51 Europe:~112* Mexico: ~7%1 Brazil 0-30% Australia: ~131 Argentina 7-15% 1 XIII IHDRW, Tenerife, June 2004; 2 Wensing AMJ, XII IHDRW, June 2003, #117; 3 Delfraissy JF,Rapport 2004

  38. Rate of Transmitted Drug Resistance by Drug Class Rate of Transmitted Drug Resistance by Chronicity of Infection All Patients 14 12 8 NRTI Rate of TDR (%) 10 6 NNRTI Acutely Infected Patients 8 4 6 PI 4 2 2 0 0 1997 1999 2001 2003 2005 1997 1999 2001 2003 2005 Year of Sample Year of Sample Declines in Transmitted Drug Resistance In the UK 10 Adapted from UK Collaborative Group on HIV Drug Resistance et al. AIDS. 2007;21:1035.

  39. GS 934: Baseline NNRTI Resistance Reduces Virologic Response No B/L NNRTI resistance B/L NNRTI resistance 100 90 84 80 73 70 60 VL < 400 copies/mL at Week 48 (%) 50 40 30 20 9 9 10 n = 206/244 1/11 177/243 1/11 0 TDF + FTC + EFV ZDV/3TC + EFV Gallant JE, et al. N Engl J Med. 2006;354:251-260.

  40. What to start with ?

  41. Efavirenz

  42. ACTG 5142: EFV vs LPV/RTV Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL, presence or absence of chronic hepatitis infection (B, C, or both), and NRTI selection Week 96 EFV 600 mg QD + 2 NRTIs* (n = 250) Antiretroviral-naive HIV-infected patients with HIV-1 RNA ≥ 2000 copies/mL (N = 753) LPV/RTV 400/100 mg BID + 2 NRTIs* (n = 253) EFV 600 mg QD + LPV/RTV 533/133 mg BID (n = 250) *NRTIs = 3TC 150 mg BID or 300 mg QD plus either ZDV 300 mg BID, d4T extended release 100 mg QD (participants < 60 kg received 75 mg QD), or TDF 300 mg QD. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

  43. ACTG 5142: HIV-1 RNA < 50 copies/mL and CD4+ Cell Count Increases at Wk 96 Multicenter, randomized, prospective, open-label phase III clinical trial EFV + 2 NRTIs (n = 250) P = .01 LPV/RTV + 2 NRTIs (n = 253) EFV + LPV/RTV (n = 250) P = .01 P = .003 287 300 100 273 89 Median CD4+ Cell CountIncrease (cells/mm3) 83 230 250 77 80 200 60 HIV-1 RNA < 50 c/mL (%)* 150 40 100 20 50 0 0 *ITT analysis including all pts on who remained on protocol; missing values were censored. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

  44. ACTG 5142: Resistance Incidence of any drug-resistance mutation or 2-class resistance higher in pts with VF on EFV-containing regimens *EFV + LPV/RTV vs LPV/RTV + NRTIs, P < .001; EFV + NRTIs vs LPV/RTV + NRTIs, P = .002. †LPV/RTV + NRTIs vs EFV + NRTIs or EFV + LPV/RTV, P < .001. ‡LPV/RTV + NRTIs vs EFV + NRTIs, P < .001; EFV + NRTIs vs EFV + LPV/RTV, P = .01. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

  45. ACTG 5142: Median Change in Lipid Levels at Wk 96 TC: HDL ratio similar at BL between arms (median: 4.3; IQR: 3.6-5.3) TC:HDL ratio significantly higher in LPV/RTV + 2 NRTIs arm vs EFV + 2 NRTIs arm at Wks 12-24 but not after Wk 24 P < .03 EFV + 2 NRTIs P < .001 LPV/RTV + 2 NRTIs 75 EFV + LPV/RTV 62† 60 57* P = .006 45 46 32 Change in Lipid Levels (mg/dL) 33 30 19 15 0 *P < .05 for LPV/RTV+ EFV vs EFV + 2 NRTIs through Wk 72. †P < .05 for LPV/RTV+ EFV vs LPV/RTV + 2 NRTIs through Wk 48. Total Cholesterol Triglycerides *P < .05 for LPV/RTV vs EFV + 2 NRTIs and LPV/RTV + 2 NRTIs. †P < .03 for all pairwise comparisons. Haubrich R, et al. AIDS 2009; 23:1109-1118.Haubrich R, et al. CROI 2007. Abstract 38.

  46. ACTG A5202 : ABC/3TC versus TDF/FTC, combined to EFV versus ATV/r in naive HIV patients Double blind Open TDF/FTC qd + Placebo ABC/3TC qd A + EFV qd 1857 naive patients VL ≥ 1000 c/ml PNo restriction on CD4 RandomiZation 1:1:1:1 Stratified on VL < ou > 100 000 c/ml ABC/3TC qd + Placebo TDF/FTC qd B + EFV qd TDF/FTC qd + Placebo ABC/3TC qd C + ATV/r qd ABC/3TC qd + Placebo TDF/FTC qd D + ATV/r qd Follow-up until last patient Week 96 Daar E, CROI 2010, Abs. 59LB

  47. ACTG 5202: Virological efficacy with ABC/3TC vs TDF/FTC In pts with screening VL < 100,000 c/mL With EFV, HR: 2.22 (1.19-4.14) Similar time to virologic failure with ABC/3TC vs TDF/FTC regardless of ATV/RTV or EFV With ATV/RTV, HR: 1.26 (0.76-2.05) With EFV, HR: 1.23; (0.77-1.96) In pts with screening VL ≥ 100,000 c/mL Shorter time to VF with ABC/3TC vs. TDF/FTC with either EFV or ATV/RTV With ATV/RTV, HR: 2.46 (1.20-5.05) Absence of VF in patients at 96 Wks for Pts with Screening VL < 100,000 copies/mL ABC/3TC TDF/FTC 100 90.3 89.2 88.3 87.4 80 60 Patients Without Virologic Failure (%) 40 20 0 ATV/RTV EFV Daar E, et al. CROI 2010. Abstract 59LB.

  48. A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72) Probability of No Virologic Failure Results similar between EFV and ATV/r arms Sax PE, et al. NEJM 2009;361:2230-2240; Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

  49. ACTG 5202: Efficacité virologique ATV/r vs EFV 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, HR: 1.13 (95% CI: 0.82-1.56) With TDF/FTC, HR: 1.01 (95% CI: 0.70-1.46) ATV/RTV EFV 100 89.8 89.0 85.3 83.4 80 60 Patients Without Virologic Failure (%) 40 20 0 ABC/3TC TDF/FTC No VF at W96 Daar E, et al. CROI 2010. Abstract 59LB.

  50. A5202: Percent of Virologic Failures with Emergence of Major Resistance Mutations ABC/3TC TDF/FTC Viral failures No baseline resistance (N) 48 76 54 63 P<0.0001 P<0.0001 Percent P=0.0003 P=0.046 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, 2010. Abst. 59LB.