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Defining the benefits of NNRTI treatment New data, new parameters

Defining the benefits of NNRTI treatment New data, new parameters. Defining the benefits of NNRTI treatment New data, new parameters. Jürgen Rockstroh, MD Professor of Medicine University of Bonn, Germany. Agenda. Housekeeping. Please ensure all mobile phones are set to silent mode

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Defining the benefits of NNRTI treatment New data, new parameters

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  1. Defining the benefits of NNRTI treatment New data, new parameters

  2. Defining the benefits of NNRTI treatmentNew data, new parameters Jürgen Rockstroh, MD Professor of Medicine University of Bonn, Germany

  3. Agenda

  4. Housekeeping • Please ensure all mobile phones are set to silent mode • Please use the question cards available and hand these to the hostesses for the discussion sessions

  5. This symposium contains information that is in the public domain but may not be in the labels of the agents discussed. Inclusion of this material does not represent recommendations for usage but is provided for educational purposes only. The views expressed in these presentations are those of the presenters and do not necessarily reflect the views of BoehringerIngelheim GmbH. Please refer to your local label before use of any agents discussed.

  6. Nevirapine Today:What Do We Know? Dr Laura WatersBrighton & Sussex University NHS Trust, Brighton, UK

  7. Disclosures • Received funding and/or honoraria from all major pharmaceutical companies working in virology

  8. Overview • First-line treatment • Current 1st line recommendations • What is the latest evidence for nevirapine first-line? • Switching • Reasons for switch • Switch recommendations and options • Benefits of switching to nevirapine

  9. Brighton cohort, ART uptake, and virological failure (VF) Patient number Year % with VF 11% 5% 4% 6% 3% 2% 2% 2% 2% 1% Personal Communication. Dr Martin Fisher, June 2011

  10. Current guidelines for initiating treatment:preferred and alternative regimens *Only when CD4<250 cells/µL in females and <400 cells/µL in males**Where there are established CV disease risk factors and a PI is required†Preferred for pregnant women only (combined with ZDV/3TC) ‡Note that specific combinations are recommended 1. Gazzard et al. HIV Medicine 2008;9:563–608; 2. http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf ; 3. Thompson et al. JAMA 2010;304:321-333; 4. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf

  11. A5202: Overall ATV/r vs EFVPrimary virologic endpoint ATV/r versus EFV with ABC/3TC: HR 1.13 (95% CI 0.82, 1.56) Prob. VF free at wk 96: 83.4 vs. 85.3%, diff -1.9% (95% CI -6.8, 2.6) TDF/FTC: HR 1.01 (95% CI 0.70, 1.46) Prob. VF free at wk 96: 89.0 vs. 89.8%, diff -0.8% (95% CI -4.9, 3.3) EFV + TDF/FTC EFV + ABC/3TC ATV/r + TDF/FTC ATV/r + ABC/3TC

  12. ARTEN involved a relatively advanced ARV-naïve population Baseline demographics Nevirapineis not currently indicated for qddosing in Europe Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; AntivirTher2011;16:333-348

  13. Treatment response by sensitivity analysis: TLOVR algorithm (ITT) 95% CI= -10.4% to 4.5%; p=0.44 100 74 80 70 60 Patients achieving treatment response (%) 40 20 0 CombinedNVP ATZ/r ARTEN: treatment response(ITT analyses; Week 48) Treatment response by primary endpoint (ITT) (two visits prior Wk 48) 95% CI= -5.9% to 9.8%; p=0.63 100 80 67 65 60 Patients achieving treatment response (%) 40 20 0 Combined NVP ATZ/r TLOVR; time to loss of virological response Nevirapineis not currently indicated for qddosing in Europe Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; AntivirTher2011;16:333-348

  14. ARTEN: grade 3−4 events of interest *Leading to discontinuation in one patient • No Grade 4 rashes • No cases of SJS, TEN, or deaths due to liver or skin toxicity Nevirapineis not currently indicated for qddosing in Europe Soriano et al; AntivirTher2011;16:333-348

  15. Swiss HIV Cohort: 2005–2008 Treatment modification 41.5 per 100PY Change for drug toxicity 22.4 per 100 PY • Reasons for toxicity change: • GI 28.9% • HSR 18.3% • CNS 17.3% • Hepatic 11.5% • Virological safety • (12 month VL <50 c/mL): • 85% switchers • 87% non-switchers Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65

  16. Time to treatment modification (all reasons)according to the cART regimen AZT/3TC + LPV/r ZDV/3TC + EFV TDF/FTC + LPV/r TDF/FTC + EFV TDF/FTC + ATZ/r ABC/3TC + EFV TDF/FTC + NVP n=1318 1.00 0.75 Probability of treatment change 0.50 p<0.001 0.25 0.00 0 3 6 9 12 Months NVP initial toxicity, but limited long-term treatment modification Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65

  17. Toxicity management Earlier ART Longer life expectancy Toxicity management will form more and more of our workload! Better understanding of toxicity Ageing & impact of HIV?

  18. Switching: EACS Guidelines “Intra-class switch preferable if drug-specific related adverse event” “PI/r to NNRTI switch for simplification, prevention or improvement of metabolic abnormalities, adherence facilitation. NVP has the advantage of its metabolic profile. EFV has the advantage of possible FDC” http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf

  19. ARTEN: impact on lipid levels Mean change from baseline to Week 48 (LOCF) in TC and TG Mean change from baseline to Week 48 (LOCF) in TC:HDL-c ratio Combined NVP Combined NVP ATZ/r ATZ/r 30 p=0.0382 p=0.0001 p=0.0001 27.8 0.15 0.13 24.4 25 0.1 0.05 19.6 20 0 Mean change (LOCF; mg/dL) 15 - 0.05 Mean change in ratio - 0.1 10 - 0.15 - 0.2 5 - 0.25 0.02 - 0.24 0 - 0.3 Total cholesterol Triglycerides Nevirapineis not currently indicated for qddosing in Europe Adapted from Podzamczeret al. HIV Med 2011;12:374-382

  20. Many studies support virological & immunological efficacy of switching • Backbone • RAVE • SWEET • BICOMBO • 3rd agent • ATARITMO • SSAT0029 • Several T20 to RAL studies

  21. Recent label change for switching to nevirapine August 2010 update to Summary of Product Characteristics: “VIRAMUNE should not be initiated in adult females with CD4 cell counts greater than 250 cells/mm3 or in adult males with CD4 cell counts greater than 400 cells/mm3, who have a detectable plasma HIV-1 RNA unless the benefit outweighs the risk.” 1 Therefore It is now possible to switch patients with undetectable viral loads (<50 copies/ml) to NVP irrespective of their CD4 cell counts ViramuneSPC, August 2010.

  22. Toxicities or patient/physician choice = TOXPC TOXPC, 2610/10186 discontinued TOXPC 18 wks, 1088/10186 discontinued HSR with detailed reasons for discontinuation, 458/6547 discontinued Switch to NVP: relative risks of NVP treatment-limiting toxicities – 7 cohorts Hazard ratios for discontinuation due to toxicity or HSRs for ARV naïve and experienced patients stratified by CD4 count and VL Kesselring et al. AIDS2009;23:1-11

  23. Long-term CNS effects with efavirenz vs raltegravir and vs rilpivirine (TMC278) Neuropsychiatric AEs by 96 weeks: Protocol 0041 Neuropsychiatric symptoms by 96 weeks: Study C2042 % patients % patients Neurological AEs of interest PsychiatricAEs *25 mg once daily dose – dose taken into Phase III trials Rilpivirine is not currently licensed for use in Europe 1. Markowitz et al. J Acquir Immune DeficSyndr2009;52:350-356; 2. Pozniak et al. AIDS 2010;24:55–65

  24. Switching from efavirenz to nevirapine: impact on CNS toxicity • Retrospective review of switch from EFV to NVP 1998-2007 (n=67) • Mean EFV exposure: 25.6 months (range: 1-96 months) • Other regimen components unchanged • Median CD4 cell count at switch: 576 cells/mm3 • All 62 patients with VL <50 copies/mL pre-switch maintained virological suppression post-switch (median 42.6 months [range: 3 months to 10 years]) • 0/67 patients who switched from EFV to NVP developed rash Ward et al. HIV 9, 2008. Glasgow UK. Poster P057

  25. Switching from EFV to NVP in ACTG A5095: switches due to CNS toxicity Patients switched to NVP due to CNS symptoms (n=47) Resolved CNS symptoms (n=46) Persistent CNS symptoms (n=1) New CNS symptoms (n=5) No recurrent CNS symptoms (n=41) No NVP discontinuations for CNS symptoms Schouten et al. Clin Infect Dis2010;50:787–791 46 Resolved CNS symptoms

  26. Comparison of CV risk factors and ultrasonography among patients treated for >5 years with NVP or EFV Statistically significant changes in a favourable direction Statistically significant changes in an unfavourable direction Subclinical carotid lesions detected by colour-Doppler ultrasonograph Maggi et al. J AntimicrobChemother2011;66:896–900

  27. SIROCCO: LDLc levels with continued EFV or switch from EFV to NPV 0.0 -0.1 -0.2 Mean change from baseline (mmol/L) -0.3 -0.4 -0.5 At 52 weeks, the data indicated a 20% decrease in 10 year relative risk for major CV events (based on the Framingham equation) Parientiet al. Clin Infect Dis 2007;45:263-266

  28. Other within class options • Etravirine • Unlicensed indication to use as a 3rd agent (ie without a PI) • Twice daily dose Etravirine SPC , Janssen-Cilag, April 2010: http://www.medicines.org.uk/emc/medicine/21185/SPC/

  29. Median number of Grade 2–4 CNS AE following a switch from EFV to ETR p<0.001 3.5 3 Baseline (n=38) 2.5 Week 12 (n=32) 2 Median number G2–4 CNS AE 1.5 1 0.5 0 Combined Analysis Waters et al. AIDS 2011;25:65-71

  30. Change in lipids 12 weeks after switching from EFV to ETR IS: immediate switch; DS: delayed switch Waters et al. AIDS 2011;25:65-71

  31. 12-year experience of NVP-containing regimens in routine clinical practice Patients receiving NVP from 1996–2008 N=592 followed up • N=231 discontinued • Reasons for discontinuation: • 42% failure • 28% side effects • 30% other causes 61% (N=361) still on NVP Median duration: 176 weeks (range: 0.3–600) • Comparative 5-year persistence from April 2003–April 2008 for most frequently prescribed 3rd agent: NVP 61%; EFV 41%; LPV/r 23% (p<0.0001) Reliquet et al. HIV Clin Trials 2010;11:110–117 46 Resolved CNS symptoms

  32. Summary • NVP combined with TDF/FTC is an effective treatment option in ARV-naïve patients when used within CD4+ cell count thresholds • NVP provides an established switch option and now can be used without CD4 restrictions in virally suppressed patients • NVP has a favourable lipid profile which may be important given that long-term morbidities include CV disease

  33. Nevirapine Tomorrow Joseph C Gathe, Jr, MD, FACP, FIDSA Therapeutic Concepts, PA Houston, TX, USA drgathe@josephgathe.com

  34. Disclosures • Received funding and/or honoraria from all major pharmaceutical companies working in virology

  35. Nevirapine Tomorrow • Can twice daily nevirapine be improved? • Historical perspective • Available data • Basic science • Clinical science • Conclusions

  36. Adherence To HAART • Adherence correlated with viral suppression, reduced rates of resistance, increased survival, and improved QoL • Predictors of poor adherence: • Treatment fatigue • Low levels of literacy • Difficulty taking medication (eg trouble swallowing pills) • Psychosocial issues (eg depression, inadequate social support) • Complex regimens (eg pill burden, dosing frequency, food requirements) • Active substance abuse • Age-related challenges (eg vision loss, cognitive impairment) • Adverse drug effects • Stigma Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166

  37. Adherence With QD vs More Frequent Dosing Correct adherence following switch to a qd regimen (EFV/3TC/D4T XR) vs continued use of a bid or more frequent ARV regimen % patients Correct adherence = % days with the correct number of doses taken, evaluated with Medication Event Monitoring System (MEMS) caps Boyle et al. HIV Clin Trials 2008;9:164–176

  38. Nevirapine Tomorrow • Can twice daily viramune be improved? • Historical perspective • Available data • Basic science • Clinical science • Conclusions

  39. Can Twice Daily Nevirapine Be Improved? • Nevirapine immediate release (NVP IR) 200 mg twice-daily (bid) is a well established component of effective triple HAART therapy1,2,3 • A nevirapine preparation given once daily (qd) would be beneficial in providing dosing symmetry with the guideline recommended qd combination nucleoside therapies3,4 • Is this possible? YES!!! Nevirapine is not currently indicated for qd dosing in Europe. 1. Gazzard et al. HIV Med 2008; 9:563–6082. EACS Guidelines 2009 http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf; 3. DHHS 2011 http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; 4.Thompson A et al. JAMA 2010; 304:321–333

  40. Past Experience With Nevirapine • Safety • 2004 2NN study (D4T/3TC) + NVP daily or NVP bid or EFV daily or NVP/EFV • Suggested some AEs may be related to extremes of NVP pharmacokinetic (PK) parameters •  Lowering NVP Cmax may reduce common AEs Nevirapine is not currently indicated for qd dosing in Europe. van Leth et al. Lancet 2004;363:1253–63

  41. Past Experience With Nevirapine • Efficacy (2NN data) • Efficacy not predicted by PK at NVP 400 mg/day dose • Patients with lowest NVP trough plasma levels did as well as patients with the highest levels • Viral decay and 48-week data supported use of NVP 3 µg/mL steady state equivalent plasma exposure as target •  Median NVP Cmin of 3 µg/mL should be target van Leth et al. HIV Clin Trials 2005;6:254-261; Leth et al. AIDS Res Hum Retroviruses 2006:22:232–239

  42. Nevirapine Tomorrow • Can twice daily viramune be improved? • Historical perspective • Available data – once daily nevirapine • Basic science • Clinical science • Conclusions Nevirapine is not currently indicated for qd dosing in Europe.

  43. The Basics Of Nevirapine eXtended Release (XR) • NVP XR should ideally show: • qd dosing • No specific dietary requirements • Lower peak plasma levels without compromising efficacy • Comparable/improved safety and maintained efficacy vs bid dosing of NVP IR • Formulation: hydrophilic polymer matrix system, widely used in oral controlled release drug delivery Nevirapine is not currently indicated for qd dosing in Europe.

  44. The Basics Of Nevirapine XR: Target PK • Steady state Cmin 3 µg/mL (>30 fold higher than IC90 of wild type virus*) • Cmax/Cmin ratio <1.5 8 NVP IR (bid)NVP XR (qd) 6 4 NVP plasma concentration (µg/mL) 2 0 IC90 0 4 8 12 16 20 24 Hours Nevirapine is not currently indicated for qd dosing in Europe. *IC90 for wild type virus = 100 ng/mL

  45. Nevirapine XR: Overview Of Development Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-pretreated HIV patients switched to NVP XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III,VERXVE 48-wk final NVP XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III,TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  46. Nevirapine XR: Overview Of Development Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-pretreated HIV patients switched to XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III,VERXVE 48-wk final NVP XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III,TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  47. The Basics Of Nevirapine XRPhase Ib: ERVIR • Objectives: • To establish the steady state PK profile of 2 different NVP XR formulations (formulation A and formulation B) under fasting and fed conditions • To compare the steady state bioavailability of the 2 different NVP XR formulations with NVP IR (200 mg bid) • Open-label, multiple-dose, parallel group study: • 4 countries: Germany, Switzerland, France, USA • Enrolled HIV-infected patients (viral load <50 c/mL; n=92) treated for >12 weeks with a stable regimen based on NVP IR 200 mg bid • Plasma samples at steady-state after IR and XR collected over 24h Nevirapine is not currently indicated for qd dosing in Europe. Quinsonet al. ICAAC 2009, Poster, Abstract A1-1310; Battegayet al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  48. ERVIR Results: NVP XR vs NVP IR 400 mg Formulation A n=24 IR 400 mg 10000 XR 400 mg fed XR 400 mg fasted 8000 6000 Mean NVP plasma conc. (ng/mL) ± SD 4000 2000 IC90 0 -4 0 4 8 12 16 20 24 (day) Time (h) Nevirapine is not currently indicated for qd dosing in Europe. *IC90 for wild type virus = 100 ng/mL Quinsonet al. ICAAC 2009, Poster, Abstract A1-1310; Battegayet al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  49. Pharmacokinetic data: relative bioavailability Bioavailability (%) • Relative to nevirapine (100%) • The bioavailability for nevirapine XR under fasted conditions was 80% • The bioavailability for nevirapine XR under fed conditions was 94% Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  50. The Basics Of Nevirapine XRCan Nevirapine Be Given QD? • Administration of NVP XR 400 mg qd resulted in extended absorption and reductions in peak levels at steady state while attaining similar troughs levels as NVP IR • NVP 400 XR formulation A exhibited better bioavailability and lower variability than other XR formulations • NVP XR formulations demonstrated similar rates of AEs and nearly all were mild • No virologic failures were observed •  NVP XR 400 mg formulation Aselected for Phase III studies Nevirapine is not currently indicated for qd dosing in Europe. Quinsonet al. ICAAC 2009, Poster, Abstract A1-1310; Battegayet al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77 Group A Group B

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