1. AIDS ΘΕΡΑΠΕΙΑ Κατευθυντήριες Οδηγίες ΓΕΩΡΓΙΟΣ ΠΑΝΟΣ BSc(Biomed.Eng.), CEng, MIET, MD, PhD, DTM&H(Lon), FRCP Αν. Καθηγητής Παθολογίας & Λοιμωδών Νοσημάτων Ιατρική Σχολή Παν/μίου Πατρών ΠΓΝΠ

2. 0-0.5 -1.5 -2 -2.5 -3 0-0.5 -1.5 -2 -2.5 -3 0-0.5 -1.5 -2 -2.5 -3 24 Week Response 1987 AZT Monotherapy1994 Two Drug Therapy 1997 Combination Therapy Including Protease Inhibitors RNA Change (Log 10 copies/mL) Fischl, NEJM, 1987 Eron, NEJM, 1995 Hammer NEJM, 1996 Gulick, NEJM, 1997 Cameron, Lancet,1998

3. EuroSIDA, 40th ICAAC 2000

4. Hammer et al., NEJM 1997, 337 (11):725 Percentage of patients (%) -50% -57% -51% -63%-49% -41% All patients BL CD4 cell count <50/mm 3 BL CD4 cell count 51−200/mm 3 0 5 10 15 20 25 AIDS/deathDeathAIDS/deathDeathAIDS/deathDeath AZT (or d4T) + 3TC (n=579) IDV + AZT (or d4T) + 3TC (n=577) Adapted from Hammer SM, et al. New Engl J Med 1997;337(11):725−733 Improved Clinical outcomes: ACTG-320

5. Reduction in Mortality Among Persons 25–44 Years Old, USA, 1982–1998 National Center for Health Statistics National Vital Statistics System *Preliminary 1998 data Introduction of PIs Unintentional injury Cancer Heart disease Suicide HIV infection Homicide Chronic liver disease Stroke Diabetes

6. Timeline of approved antiretrovirals Source: ClinicalCareOptions

7. ARV adherence milestones TID+TIDBDOD 1987 ’88 ’89 ’90 ’91 ’92 ’93 ’94 ’95 ’96 ’97 ’98 ’99 ’00 ’01 ’02 ’03 ’04 ’05 ’06 ’07 ’08 ’09 ’10 ‘11 NNRTI NRTI PI Fusion-I CCR5-I Integrase-I ddI EC http://www.fda.gov/oashi/aids/virals.html AZT ddI d4T 3TC ddC ABC Combivir Trizivir Nevirapine Efavirenz FTC Tenofovir Kivexa Truvada Raltegravir Atripla Etravirine SQV HG NFV IDV RTV SQV SG APV LPV/r ATV fAPV Fuzeon TPV DRV Maraviroc Delavirdine

8. New Classes Fusion Inhibitors Enfuvirtide (T-20) R5 Inhibitors Maraviroc Integrase Inhibitors Raltegravir Elvitegravir Dolutegravir Protease Inhibitors Atazanavir Darunavir Fos-Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTIs Delavirdine Efavirenz Nevirapine Etravirine Rilpivirine Classes of Drugs available for HIV therapy

9. 0 102030405060708090 100 % with VL < 50 at week 48 Boosted PI NNRTI NRTI Unboosted PI Bartlett JA et al. Abstract 586. 12th CROI 2005 The primary driver of virologic response is regimen potency. Pill count was not consistently associated with virologic responses Collated results of HAART studies

10. NRTI PI/r (DRV/r) PI NNRTI (RPV) NNRTI PI-containing NNRTI- containing NRTI-saving NRTI PI and NNRTI- saving ++ ++ + ++ Options for first line HAART NRTI and IIs NRTI IIs ++ Adapted from EACS Guidelines version 8.0 (October 2015

11. ART CC: Supports Initiating ART at CD4 Threshold of 350 cells/mm 3 Analysis of 15 cohorts from US and Europe (ART Cohort Collaboration) (N = 24,444) Sterne J, et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only. 0.5 1.0 2.0 4.0 500400300100 CD4 Threshold (cells/mm 3 ) HR for AIDS or Death* 200 0 ComparisonHR* (95% CI) 1-100 vs 101-2003.35 (2.99-3.75) 101-200 vs 201-3002.21 (1.91-2.56) 201-300 vs 301-4001.34 (1.12-1.61) 251-350 vs 351-4501.28 (1.04-1.57) 351-450 vs 451-5500.99 (0.76-1.29) *Adjusted for lead-time and unobserved events.

12. NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART 1. Kitahata MM, et al. ICAAC/IDSA 2008. Abstract 896b. 2. Kitahata MM, et al. CROI 2009. Abstract 71. Parameter Associated With Risk of Death Relative Hazard (95% CI) 1.02.50.1 P Value Deferral of HAART until < 350 cells/mm 3 (vs starting at 350-500 cells/mm 3 ) [1] 1.7<.001  Female sex1.1.290  Older age (per 10 yrs)1.6 <.001  Baseline CD4+ cell count * 0.9.083 Deferral of HAART until < 500 cells/mm 3 (vs starting at ≥ 500 cells/mm 3 ) [2] 1.6 <.001  Female sex 1.2.117  Older age (per 10 yrs) 1.6<.001  Baseline CD4+ cell count* 1.0.696 *Per 100 cell/mm 3 increase.

13. SMART: Immediate Therapy Reduces Risk of OD, Serious Non-AIDS Events Immediate group experienced substantially fewer events compared with deferred group – Excess risk associated with deferring therapy: 5.4 events/100 person-yrs Emery S, et al. J Infect Dis. 2008;197:1133-1144. Event, n (Rate per 100 Person-Yrs) Deferred Arm (n = 228) Immediate Arm (n = 249) HR (DC/VS) 95% CIP Value OD/death15 (4.8)5 (1.3)3.51.3-9.6.02 OD only11 (3.5)4 (1.1)3.31.0-10.3.04 Serious non- AIDS events 12 (3.9)2 (0.5)7.01.6-31.4.01 Composite21 (7.0)6 (1.6)4.21.7-10.4.002

14. Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level Moore RD, et al. Clin Infect Dis. 2007;44:441-446. Published by The University of Chicago Press. Copyright © 2009. University of Chicago Press. All rights reserved. http://www.journals.uchicago.edu/toc/cid/current. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192. Reproduced with permission. ATHENA National Cohort [2] Johns Hopkins HIV Clinical Cohort [1] Yrs on HAART Median CD4+ Cell Count (cells/mm 3 ) 1000 BL CD4+ Cell Count 04896144192240288336 Wks From Starting HAART 200 400 600 800 0 1000 > 500 351-500 201-350 51-200 < 50 BL CD4+ Cell Count 200 400 600 800 0 0 12345 > 350 < 200 201-350 6

15. Survival of Patients with CD4 Counts ≥ 500 cells/mm 3 for >5 Years is Similar to the General Population Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72–77. Duration of Follow-up with CD4 > 500 cells/mm 3 (Yrs) N Deaths n Standardized Mortality Ratio (95% CI) 01208372.5 (1.8-3.5) 11156292.1 (1.4-3.1) 21083262.2 (1.4-3.2) 31031222.1 (1.3-3.2) 4967182.1 (1.3-3.4) 5864121.9 (1.0-3.2) 676320.5 (0.1-1.6) 761010.5 (0.0-2.6) Standardized Mortality Ratio = Mortality in HIV-infected patients / Mortality in General Population

16. The INSIGHT START Study Group (NEJM 2015) Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection Initiation of ART in HIV(+) adults with CD4>500c/μl provided net benefits over starting therapy in HIV(+) patients when CD4 <350c/μl The primary composite end point was any serious AIDS-related event, serious non-AIDS event or death from any cause Primary end point occurred 1.8% in the immediate initiation group Vs 4.1% in the deferred initiation group (0.6 Vs 1.38 events per 100 person years)

19. CURRENT EUROPEAN (EACS) ANTIRETROVIRAL THERAPY GUIDELINES (2015) EACS guidelines, version 8.0 (October 2015)

20. Retrovirus life cycle Entry inhibitors ENFMRV VCV Reverse transcriptase inhibitors ZDVNVP ddIDLV ddCEFV d4T3TC FTCABC TDF Integrase inhibitors GS9137 MK0518 others Protease inhibitors SQVIDV RTVNFV FPVLPV ATVTPV DRV Maturation inhibitor bevirimat

25. Treatment of HIV-positive Pregnant Women

26. Adverse Effects of ARVs & Drug Classes

42. SWITCHING ANTIRETROVIRAL REGIMENS I.In Virally Suppressed Patients II. In Patients with Virological Failure

45. Virological Failure

47. ΣΥΜΠΛΗΡΩΜΑΤΙΚΕΣ ΓΝΩΣΕΙΣ

48. 4321 NRTISZDVABCddITDF FTC3TCddC d4T NNRTIsNVPDLVETV EVF PIsIDV/rDRV/rATV/rNFV FPV/rATVRTV IDVFPVSQV/r LPV/rSQV Fusion/Entry Inhibitors MVC Integrase inhibitors RALENF Letendre, S et al. 17 th CROI 2010. Abstract 430. 2010 updated score for ART efficacy in CSF