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Initial Antiretroviral Therapy

Initial Antiretroviral Therapy. Manuel Battegay Infectious Diseases & Hospital Epidemiology University Hospital Basel. Special thank to Luigia Elzi for helping preparing this lecture. Outline. Natural history of HIV Aims of antiretroviral therapy (cART) When to start What to start

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Initial Antiretroviral Therapy

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  1. Initial Antiretroviral Therapy Manuel Battegay InfectiousDiseases & Hospital Epidemiology University Hospital Basel Special thankto Luigia Elzi for helping preparingthislecture

  2. Outline • Natural history of HIV • Aims of antiretroviral therapy (cART) • When to start • What to start • Monitoring • When to change

  3. Natural history of HIV acute chronic AIDS HIV viral load CD4 Years Saag MS et al, Nat Medicine; Mellors J et al, Science, 1996

  4. Goals of ART Increase in CD4 cell count HIV virologic suppression <50 copies/mL Improved immunologic function Reduction in opportunistic infections and tumors Prevention of transmission

  5. ART improves life expectancy 1.0 0.8 HIV-infectedbefore1996 0.6 Cumulative mortality 0.4 HIV-infected 2004–2006 0.2 General population2004–2006 0.0 0 2 4 6 8 10 12 14 Time after seroconversion (Years) Assumptions: Start ART if CD4 cell count <350 cells/µL 90% virologic suppression <50 copies/mL Hammer SM et al, ACTG 320, N Engl J Med, 2007; Egger et al, SHCS, BMJ 2007; Bhaskaran K et al, CASCADE, JAMA 2008; Hogg et al The ART-CC, Lancet 2008; Elzi L et al, ArchIntMed 2010

  6. No difference in mortality HIV vs non-HIV • 80’642 and 3’280 HIV-infected persons • No significant difference in mortality in comparison to ‘general population’, if • ART • Well controlled virus • No illicit drug use • No prior AIDS Implications for care, work, life C Lewden et al., Int J Epidemiol 2012, Rotger AJ, AIDS, 2013

  7. Transmission reduction with ARTMyron Cohen et al, New England Journal of Medicine, 2011 • Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, United States, Zimbabwe • 1763 discordant couples (HIV+/HIV-) • Reduction, if early ART 96% ! • 1 Transmission early ART • 27 Transmissions Standard ART ChronicDiseasesClinicIfakara IHI, Swiss TPH, USB

  8. When to start Symptomatic HIV disease CDC stage B/C Pregnancy Readiness Primary HIV infection Asymptomatic HIV infection

  9. ART-CC: Supports Initiating ART at CD4 threshold of 350 cells/mm3 4.0 2.0 HR for AIDS or Death* 1.0 0.5 0 500 400 300 100 200 *Adjusted for lead-time and unobserved events CD4 Threshold (cells/mm3) N=24,444 (15 cohorts from US and Europe) Sterne et al. Lancet 2009

  10. SCRIPT ONLY HIV Causal Collaboration ART-naive, CD4>500, no AIDS, N= 20,970 Nochanges in mortality but in AIDS-definingeventswithstarting ART atincreasing CD4 (>450 cells/µl) Cain et al., Ann Intern Med, 2011:154:509-115

  11. 5-year outcome by CD4 at starting ART All-causemortality AIDS events Delaying ART initiation until CD4<350 is estimated to result in a 38% increase of AIDS-events or death compared with starting ART at CD4 of 500, i.e. 48 pts need to initiate ART at CD4 500 to prevent 1 AIDS/death Cain et al., Ann Intern Med, 2011:154:509-115

  12. EACS Guidelines EACS Guidelines Version 6.1

  13. When to Start Therapy: Balance Now Favors Earlier Antiretroviral Therapy • Drug toxicity • Preservation of limited Rx options • Risk of resistance (and transmission of resistant virus) • ↑ potency, durability, simplicity, safety of current regimens • ↓ emergence of resistance • ↓ toxicity with earlier therapy • ↑ subsequent treatment options • Risk of uncontrolled viremia • Near normal survival if start earlier • ↓ transmission Early ART Delayed ART Slide from Joel E. Gallant, MD, MPH

  14. Evolution of CD4+ Count Criteria for Starting Antiretroviral Therapy in Asymptomatic Persons with Human Immunodeficiency Virus Infection, According to Different Guidelines. ART Guidelines De Cock K, N Engl J Med, 2013

  15. WHO-2013: Changes in Recommendations When to Start in Adults

  16. WHO-2013: Recommendations: CD4 Independent Conditions

  17. Is the patient ready for ART ? «I wouldliketotalkabout HIV medication» Pleasewait … «What do youthinkaboutit?» Patientfactors: Depression Drug, alcoholaddiction Cognitiveproblems Low healthliteracy Systemfactors: Healthinsurance Continuityofdrugsupply Low socialsupport

  18. SCRIPT ONLY EACS Guidelines

  19. Perception v Reality Slide courtesy Mark Nelson, London

  20. Atazanavir, Lopinavir, Darunavir, Ritonavir, Indinavir, Saquinavir, Fosamprenavir, Nelfinavir, Tipranavir Maraviroc Enfuvirtide Tenofovir, Abacavir, Lamivudine, Emtricitabine, Didanosin, Zidovudine Efavirenz Nevirapine Etravirine Rilpivirine Raltegravir Elvitegravir Dolutegravir Volberding et al., Lancet 2010

  21. What to start in 2013 6 drug classes • NRTIs • Abacavir • Didanosine • Emtricitabine • Lamivudine • Stavudine • Tenofovir • Zidovudine • NNRTIs • Efavirenz • Nevirapine • Etravirine • Rilpivirine • Protease Inhibitors • Atazanavir • Darunavir • Fos-Amprenavir • Indinavir • Lopinavir • Nelfinavir • Ritonavir • Saquinavir • Tipranavir • New Classes • Fusion Inhibitors • Enfuvirtide • R5 Inhibitors • Maraviroc • Integrase Inhibitors • Raltegravir • Elvitegravir Slide courtesy Mark Nelson, London

  22. How to start NNRTI Efavirenz (EFV) Nevirapin (NVP) Etravirin (ETV) Rilpivirin (RPV) PI NRTI Amprenavir (APV) Atazanavir (ATV) Indinavir (IDV) Lopinavir/r (LPV) Saquinavir (SQV) Ritonavir (RTV) Nelfinavir (NFV) Tipranavir (TPV) Darunavir (DRV) 2 NRTI + 1 NNRTI Abacavir (ABC) Didanosin (DDI) Emtricitabin (FTC) Lamivudin (3TC) Stavudin (D4T) Tenofovir (TDF) Zidovudin (ZDV) TDF/FTC (Truvada®) ABC/3TC (Kivexa®) ZDV/3TC (Combivir®) 2 NRTI + 1 PI IntegraseInh. 2 NRTI + 1 Int-Inh Raltegravir(RGV) Elvitegravir (EVG) Dolutegravir (DGV)

  23. Considerations When Selecting First-line Antiretroviral Therapy Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  24. Transmission of HIV resistance Kim D, et al, CROI, 2013; Monge S, et al, CMI, 2012, UK Collaborative Group on HIV Drug Resistance, BMJ, 2012;

  25. Trade-Offs: Efavirenz-Based ART ACTG 5202: 96-Wk Results ATV/RTV 100 89.8 89.0 EFV 85.3 83.4 80 60 Patients Without Virologic Failure (%) 40 20 0 ABC/3TC TDF/FTC Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  26. SCRIPT ONLY Trade-Offs: Rilpivirine HIV-1 RNA < 50 copies/mL at Wk 48 Among Pts With BL HIV-1 RNA > 100,000 c/mL Tx Failure in ECHO and THRIVE 14 15 -3.6 (-9.8 to +2.5) 100 12 81 82 80 79 76 77 80 8.5 9 8 RPV + TDF/FTC 60 Patients (%) Patients (%) EFV + TDF/FTC 6 40 4.1 3 20 246/318 285/352 125/165 149/181 121/153 136/171 346 n = 686 682 686 682 0 0 VF AE Pooled THRIVE ECHO

  27. Trade-Offs: Darunavir/Ritonavir ARTEMIS Trial Wk 48 Wk 96 VL < 50 copies/mL (%) 100 84 79 78 80 71 60 40 20 0 LPV/RTV LPV/RTV DRV/RTV DRV/RTV Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  28. Trade-Offs: Atazanavir/Ritonavir CASTLE Trial VL < 50 copies/mL (%) Wk 48 Wk 96 100 78 76 74 80 68 60 40 20 0 LPV/RTV LPV/RTV ATV/RTV ATV/RTV

  29. Trade-Offs: Raltegravir-Based ART EFVRAL STARTMRK[1] 100 86 81 76 75 80 82 79 60 69 67 VL < 50 copies/mL (%) ∆ = +9.0 (95% CI: 1.6-16.4) Noninferiority P < .001 40 20 0 0 16 48 72 96 120 156 192 Wks Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  30. SCRIPT ONLY “Quad”: Cobicistat-Boosted EVG + TDF/FTC vs EFV/TDF/FTC in Naive Pts • Cobicistat (GS-9350, COBI): CYP3A inhibitor (boosting agent) • Elvitegravir (EVG): integrase inhibitor Wk 24 primary endpointanalysis 100 90 Wk 48 83 80 ITT, M = F 60 ART-naive pts with CD4 ≥ 50, VL ≥ 5000, no NRTI, NNRTI or PI resistance (N = 71) EVG/COBI/TDF/FTC(n = 48) HIV-1 RNA < 50 c/mL (%) 40 EVG/COBI/TDF/FTC EFV/TDF/FTC Wk 24 stratum-weighted difference: +5% (95% CI: -11.0% to 21.1%) EFV/TDF/FTC(n = 23) 20 0 0 4 8 12 16 20 24 Wk Cohen C, et al. AIDS. 2011;25:F7-12. Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  31. Patients With High HIV-1 RNA ACTG 5095 ATCG 5202 at 96 Wks Favors4 drugs ATV/RTV 3 drugs EFV Overall < 30,000 100 89.8 89.0 85.3 83.4 30,000-99,999 80 Pretreatment HIV-1 RNA Level (copies/mL) 60 100,000-299,999 Patients Without Virologic Failure (%) 40 300,000-749,999 20 ≥750,000 Interaction: P = .63 0 ABC/3TC TDF/FTC 0.35 0.66 1.00 1.75 2.85 HR Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  32. ART and Effects on Lipids • RAL appears to be neutral with respect to lipid changes[1] • EFV associated with greater lipid change than RAL in STARTMRK[1] • EFV associated with greater cholesterol changes than ATV/RTV in ACTG 5202[2] • Both ATV/RTV and DRV/RTV associated with lesser lipid change than LPV/RTV[3,4] 1. Lennox J, et al. Lancet. 2009;374:796-806 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 3. Molina JM, et al. Lancet. 2008;372:646-655. 4. Ortiz R, et al. AIDS. 2008;22:1389-1397.

  33. ART and Renal Function • TDF may be associated with declining renal function over time in some patients[1] • Some studies suggest greater decline in renal function with TDF + boosted PIs vs TDF + NNRTIs[2,3] • Cumulative exposure to ATV/RTV associated with increased risk of chronic kidney disease in cohort study; risk reversed upon stopping[4] • In clinical studies of RAL, no clinically important PK differences have been observed between subjects with severe renal impairment and healthy subjects[5] 1. Tenofovir [package insert]. September 2011. 2. Morlat P, et al. IAS 2011. Abstract WEPDB0104. 3. Gallant JE, et al. AIDS. 2009;23:1971-1975. 4. Mocroft A, et al. AIDS. 2010;24:1667-1678. 5. Raltegravir [package insert]. November 2011. Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  34. Comorbidities

  35. Dosing Comparisons Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  36. SCRIPT ONLY Convenience • Once-daily versus twice-daily • One pill: TDF-FTC-EFV (Atripla®); TDF-FTC-RPV (Eviplera®, Complera®); TDF-FTC-EVG-COB (Stribild®) • To take with food: rilpivirin, elvitegravir, atazanavir, darunavir, saquinavir • To take before sleeping: efavirenz • Sirup or soluble tablets available

  37. Which Patient for Which Regimen? Adapted from slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  38. SCRIPT ONLY Which Patient for Which Regimen? Slide, CCO, Jose R. Arribas, MD, and Anton L. Pozniak, MD

  39. EACS Guidelines 2012

  40. ART according to study sites n=1,957 Treatment-naive ART started 2005-2010 SHCS sites Elzi & Battegay et al., Arch Intern Med, 2012

  41. Different treatment are very efficent in the ‘real world’ Individualisation Gender, Drug use, Hepatitis, CVD, high VL Elzi & Battegay et al., Arch Intern Med, 2012

  42. Drug specific toxicity

  43. Safety and tolerability of current antiretroviral regimens in RCTs SCRIPT ONLY 1. Malan N et al IAS 2007. Abstract WEPEB024. 2. Arribas JR et al IAS 2007. Abstract WEPEB029. 3. Eron J Jr et al Lancet. 2006;368:476-482. 4. Ortiz R et al, AIDS, 2008. 5. Molina JM, et al, Lancet 2008. 6. Smith K, et al CROI 2008. Abstract 774. 7. Walmsley SL, et al EACS 2007. Abstract PS1.4.

  44. Monitoring • Side effects • Tolerability • Toxicity • Viral load after 1 month, 3 and 6 months • CD4 measuring frequency depending on starting point: more frequently if below 200, otherwise same as for VL • VL failure: <50 copies/mL after 6 months on ART

  45. Main reason for ART modification % N=1318 30% of patients modify ART during the first year, 50% of these because of intolerance/toxicity Elzi et al., Arch Intern Med, 2010

  46. Co-medication in the SHCS 10% methadone cardiovascular/ diabetes drugs 56% vitamins/minerals 11% analgesics 11% gastrointestinal anti-infectives 11% CNS agents 31% 12% immunosuppressants 4% hormones 3% bronchodilatators 3% antihistamines 2% herbals 1% • 1497 patients • 68% with ≥ 1 co-medication • 40% ≥ 1 drug-drug interaction Interactions more frequent >50 y Marzolini & Battegay et al., Antiviral Therapy, 2010, Marzolini C et al. J Antimicrob Chemother 2011

  47. Drug-drug interactions www.hiv-druginteractions.org

  48. Suboptimal adherence leads to virologic failure and HIV progression Adherence n=3173 Pat. TR Glass et al., J Acquir Immune Defic Syndr. 2010

  49. When to change • Virologicfailure - Non adherence - Drug-druginteractions - Intercurrentinfections • Intolerance, toxicity • Convenience (simplification)

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