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

2. Jürgen Rockstroh, MD Professor of Medicine University of Bonn, Germany

3. Agenda TimeTitleSpeaker 10.15–10.20Welcome and introductionJürgen Rockstroh 10.20–10.45Nevirapine today: what do we know? Laura Waters 10.45–11.15Nevirapine tomorrowJoe Gathe 11.15–11.45Defining success in HIV treatment: should we broaden the parameters? Vicente Soriano 11.45–12.15Discussion and debate sessionAll

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 Boehringer Ingelheim GmbH. Please refer to your local label before use of any agents discussed.

6. Nevirapine Today: What Do We Know? Dr Laura Waters Brighton & 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 1 st 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) % with VF 11% 5% 4% 6% 3% 2% 2% 2% 2%1% Personal Communication. Dr Martin Fisher, June 2011 Year Patient number

10. Current guidelines for initiating treatment: preferred and alternative regimens BHIVA (2008) 1 EACS V5.4 (2011) 2 IAS-USA (2010) 3 DHHS (2011) 4‡ NRTI preferred TDF/FTC ABC/3TC TDF/FTC ABC/3TC TDF/FTC NRTI alternative ddI ZDV ZDV/3TC ddI/3TC or FTC ABC/3TC ZDV/3TC 3 rd drug preferred EFVEFV, NVP* ATV/r, LPV/r, DRV/r, SQV/r, RAL EFV ATV/r, DRV/r RAL EFV ATV/r, DRV/r RAL LPV/r † 3 rd drug alternative LPV/r, FPV/r, ATZ/r, SQV/r, NVP*, ATZ ** SQV/r, FPV/rLPV/r, FPV/r, MVC NVP*, FPV/r, LPV/r 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 *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

11. ATV/r vs EFV Primary virologic endpoint A5202: Overall 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 NVP qd (n=188) NVP bid (n=188) ATZ/r (n=193) Mean age (years)38.440.037.6 Male gender (%)80.986.783.9 Caucasian (%)78.281.979.8 Western Europe (%)72.371.868.4 Hepatitis B or C at screening (%)11.210.611.9 MSM/IDU (%)50.5/5.954.8/5.952.8/6.7 pHIV-RNA >10 5 log copies/mL (%)62.8 65.8 Mean CD4+ count (cells/  L) 176.8187.4187.8 CD4+ count <50 cells/  L (%) 7.49.06.2 Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; Antivir Ther 2011;16:333-348 Nevirapine is not currently indicated for qd dosing in Europe

13. ARTEN: treatment response (ITT analyses; Week 48) Patients achieving treatment response (%) Treatment response by primary endpoint (ITT) (two visits prior Wk 48) 95% CI= -5.9% to 9.8%; p=0.63 6765 0 20 40 60 80 100 ATZ/rCombined NVP 95% CI= -10.4% to 4.5%; p=0.44 74 70 0 20 40 60 80 100 ATZ/rCombined NVP Treatment response by sensitivity analysis: TLOVR algorithm (ITT) Patients achieving treatment response (%) Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; Antivir Ther 2011;16:333-348 Nevirapine is not currently indicated for qd dosing in Europe TLOVR; time to loss of virological response

14. ARTEN: grade 3−4 events of interest Combined NVPATZ/r DAIDS Grade (% patients) G3G4G3G4 ALT3.73.51.60.0 AST4.02.1 0.5 Total bilirubin1.6 44.6*8.8 *Leading to discontinuation in one patient Soriano et al; Antivir Ther 2011;16:333-348 Nevirapine is not currently indicated for qd dosing in Europe Grade 3−4 % Combined NVPATZ/r Rash 1.60.0  No Grade 4 rashes  No cases of SJS, TEN, or deaths due to liver or skin toxicity

15. Swiss HIV Cohort: 2005–2008 Treatment modification 41.5 per 100PY Change for drug toxicity 22.4 per 100 PY Virological safety (12 month VL <50 c/mL): 85% switchers 87% non-switchers Reasons for toxicity change: GI 28.9% HSR18.3% CNS 17.3% Hepatic 11.5% Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65

16. 0.00 0.25 0.50 0.75 1.00 Probability of treatment change 036912 Months ZDV/3TC + EFV TDF/FTC + EFV ABC/3TC + EFV AZT/3TC + LPV/r TDF/FTC + LPV/r TDF/FTC + ATZ/r TDF/FTC + NVP Time to treatment modification (all reasons) according to the cART regimen p<0.001 Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65 NVP initial toxicity, but limited long-term treatment modification n=1318

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

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:HDL-c ratio Mean change in ratio p=0.0001 -0.24 0.13 -0.3 -0.25 -0.2 -0.15 -0.1 -0.05 0 0.1 0.15 Combined NVP ATZ/r Adapted from Podzamczer et al. HIV Med 2011;12:374-382 Nevirapine is not currently indicated for qd dosing in Europe 24.4 0.02 19.6 27.8 0 5 10 15 20 25 30 Total cholesterolTriglycerides Combined NVPATZ/r Mean change from baseline to Week 48 (LOCF) in TC and TG p=0.0382p=0.0001 Mean change (LOCF; mg/dL)

20. Many studies support virological & immunological efficacy of switching  Backbone  RAVE  SWEET  BICOMBO  3 rd 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/mm 3 or in adult males with CD4 cell counts greater than 400 cells/mm 3, 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 Viramune SPC, August 2010.

22. Switch to NVP: relative risks of NVP treatment-limiting toxicities – 7 cohorts Kesselring et al. AIDS 2009;23:1-11 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 Hazard ratios for discontinuation due to toxicity or HSRs for ARV naïve and experienced patients stratified by CD4 count and VL

23. Long-term CNS effects with efavirenz vs raltegravir and vs rilpivirine (TMC278) 1. Markowitz et al. J Acquir Immune Defic Syndr 2009;52:350-356; 2. Pozniak et al. AIDS 2010;24:55–65 % patients Rilpivirine is not currently licensed for use in Europe Neuropsychiatric AEs by 96 weeks: Protocol 004 1 Neuropsychiatric symptoms by 96 weeks: Study C204 2 Neurological AEs of interest Psychiatric AEs % patients *25 mg once daily dose – dose taken into Phase III trials

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/mm 3  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 On EFV before switch After switch from EFV to NVP Neuropsychiatric side effects (n)4313 Sleep disturbance (n)349 Ward et al. HIV 9, 2008. Glasgow UK. Poster P057

25. Switching from EFV to NVP in ACTG A5095: switches due to CNS toxicity Schouten et al. Clin Infect Dis 2010;50:787–791 No NVP discontinuations for CNS symptoms 46 Resolved CNS symptoms Patients switched to NVP due to CNS symptoms (n=47) Resolved CNS symptoms (n=46)Persistent CNS symptoms (n=1) No recurrent CNS symptoms (n=41) New CNS symptoms (n=5)

26. Comparison of CV risk factors and ultrasonography among patients treated for >5 years with NVP or EFV CV risk factor (median value) Nevirapine (n=156)Efavirenz (n=120) BaselineFollow upPBaselineFollow upP TC (mg/dL)1991890.00811771940.0001 HDLc (mg/dL)44.747.10.007643.244.80.3938 LDLc (mg/dL)1261180.00541081160.01 TG (mg/dL)1841360.00011442300.0001 BMI (kg/m 2 )24.123.80.09723.624.20.002 Glucose (mg/dL)94930.4694941010.0025 Ultrasonography (% patients) BaselineFollow upPBaselineFollow upP Normal69640.802977260.0001 Pathological31362374 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 Antimicrob Chemother 2011;66:896–900

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

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

30. Change in lipids 12 weeks after switching from EFV to ETR Mean Baseline mmol/L (IS arm) Mean Baseline mmol/L (DS arm) Mean change mmol/L (SD) (both arms) p-value Total cholesterol 5.335.26-0.64 (1.02) <0.001 HDL- cholesterol 1.341.09-0.04 (0.21) ns LDL- cholesterol 3.583.41-0.58 (1.09) 0.021 Triglycerides1.451.73-0.19 (0.62) 0.092 Waters et al. AIDS 2011;25:65-71 IS: immediate switch; DS: delayed switch

31. NCD4 (cells/µL) Day 0, median CD4 (cells/µL) Latest value, median VL <200 c/mL Day 0, % VL <200 c/mL Latest value (%) Naïve67271551097 Failure54289565096 Switch240461547100 12-year experience of NVP-containing regimens in routine clinical practice Reliquet et al. HIV Clin Trials 2010;11:110–117 46 Resolved CNS symptoms Patients receiving NVP from 1996–2008 N=592 followed up 61% (N=361) still on NVP Median duration: 176 weeks (range: 0.3–600) N=231 discontinued Reasons for discontinuation: 42% failure 28% side effects 30% other causes  Comparative 5-year persistence from April 2003–April 2008 for most frequently prescribed 3 rd agent: NVP 61%; EFV 41%; LPV/r 23% (p<0.0001)

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: 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 Low levels of literacy Age-related challenges (eg vision loss, cognitive impairment) Active substance abuse Stigma Difficulty taking medication (eg trouble swallowing pills) Adverse drug effects Treatment fatigue Complex regimens (eg pill burden, dosing frequency, food requirements) Psychosocial issues (eg depression, inadequate social support)

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

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 therapy 1,2,3  A nevirapine preparation given once daily (qd) would be beneficial in providing dosing symmetry with the guideline recommended qd combination nucleoside therapies 3,4  Is this possible? YES!!! 1. Gazzard et al. HIV Med 2008; 9:563–608 2. 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 Nevirapine is not currently indicated for qd dosing in Europe.

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 C max may reduce common AEs van Leth et al. Lancet 2004;363:1253–63 Nevirapine is not currently indicated for qd dosing in Europe.

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 C min 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 Hours NVP plasma concentration (µg/mL) 0 2 4 6 8 04812162024 NVP IR (bid) NVP XR (qd)  Steady state C min 3 µg/mL (>30 fold higher than IC 90 of wild type virus*)  C max /C min ratio <1.5 Nevirapine is not currently indicated for qd dosing in Europe. *IC 90 for wild type virus = 100 ng/mL IC 90

45. Nevirapine XR: Overview Of Development Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR- pretreated HIV patients switched to NVP XR Q4 2006–Q2 2007 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 Colonic absorption Q2–Q4 2005 Nevirapine is not currently indicated for qd dosing in Europe.

46. Nevirapine XR: Overview Of Development Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR- pretreated HIV patients switched to XR Q4 2006–Q2 2007 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 Colonic absorption Q2–Q4 2005 Nevirapine is not currently indicated for qd dosing in Europe.

47. The Basics Of Nevirapine XR Phase 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 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 Quinson et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay et al. 12 th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77 Nevirapine is not currently indicated for qd dosing in Europe.

48. ERVIR Results: NVP XR vs NVP IR 400 mg Formulation A -404812162024 Time (h) (day) Mean NVP plasma conc. (ng/mL) ± SD 0 2000 4000 6000 8000 10000 IR 400 mg XR 400 mg fasted XR 400 mg fed Quinson et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay et al. 12 th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77 Nevirapine is not currently indicated for qd dosing in Europe. IC 90 *IC 90 for wild type virus = 100 ng/mL n=24

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. 12 th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

50. The Basics Of Nevirapine XR Can 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 Group A Group B  NVP XR 400 mg formulation A selected for Phase III studies Nevirapine is not currently indicated for qd dosing in Europe. Quinson et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay et al. 12 th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

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

52. Nevirapine XR: overview of clinical development Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Phase Ib: ERVIR multiple dose PK (to steady state), NVP IR- pretreated HIV patients switched to XR Q4 2006–Q2 2007 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 Colonic absorption Q2–Q4 2005 Nevirapine is not currently indicated for qd dosing in Europe.

53. Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice daily in treatment-naïve HIV-1 infected patients J Gathe, J Andrade-Villaneuva, S Santiago et al. Antivir Ther 2011;16: in press

54. VERXVE: Objectives And Study Design Objective: –To evaluate the efficacy and safety of NVP XR 400 mg qd vs NVP IR 200 mg bid, in ARV treatment-naïve, HIV–1-infected patients Study design: –48 week, double-blind, double-dummy, non-inferiority study Subjects: –NVP eligible adult subjects with CD4/mm 3 counts of 50–400 for men and 50–250 for women –Baseline viral load (VL) stratification (≤100,000 vs >100,000 copies/mL) Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

55. Eligible patient Screening NVP IR 200 mg qd + TDF/FTC for 14 days Randomisation Group A (n=505) 400 mg qd NVP XR + TDF/FTC Group B (n=506) 200 mg bid NVP IR + TDF/FTC VERXVE Study Schema Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

56. VERXVE: Study Endpoints Primary endpoint: –Sustained virologic response at 48 weeks – defined as VL <50 copies/mL prior to and at week 48, without virologic rebound or change of ARV therapy Secondary endpoints: –Time-to-loss of virologic response (TLOVR) –Time to new AIDS or AIDS-related progression event or death –AEs, SAEs, AEs leading to discontinuation; laboratory parameters –PK parameters – NVP plasma trough concentrations –Genotypic resistance associated with virologic failure Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

57. Proportion of Virologic Responders (FAS; %) AD 4.9% 95% CI: −0.1%, 10.0% AD 2.3% 95% CI: −6.6%, 11.1% AD 6.6% 95% CI: 0.7%, 12.6% Virologic response was independent of age, gender, race or geographic region Mean CD4+ increase from baseline at Week 48: NVP IR 181 cells/mm 3 ; NVP XR 192 cells/mm 3 FAS: full analysis set AD: adjusted difference n=506n=505n=203n=194 n=303 n=311 VERXVE: Virologic Response at Week 48 Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

58. Weeks Mean dose trough NVP (µg/mL) 10 th percentile trough concentration for Viramune XR 0 1 2 3 4 5 6 468121624324048 NVP IR (4.11 µg/mL) NVP XR (3.35 µg/mL) (~38-fold higher) IC 90 for wild type HIV-1 virus* VERXVE: Multiple Dose Trough Concentrations NVP IR and NVP XR Geometric Mean, µg/mL Boehringer Ingelheim: Data on file Nevirapine is not currently indicated for qd dosing in Europe. *IC 90 for wild type virus = 100 ng/mL

59. Selected AEs Of Interest During The Randomisation Phase (Post-NVP IR Lead-In) NVP IR, n (%)NVP XR, n (%) Treatment-related rash (all grades) 25 (4.9)29 (5.7) Grade 3 rash3 (0.6) Stevens Johnson Syndrome 3 (0.6)*0 (0.0) Any hepatic event46 (9.1)28 (5.5) Symptomatic hepatic events 22 (4.3)14 (2.8) *2 grade 3 and 1 grade 4 cases. No instances of SJS or grade 4 rash in the nevirapine XR group Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

60. VERXVE: Conclusions The VERXVE pivotal trial demonstrated: –Non-inferior efficacy for NVP XR compared with NVP IR independent of baseline viral load, age, race, gender, region, HIV-1 subtype or CDC class –No new AEs identified, reflecting similar safety and tolerability profiles for both formulations Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

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

62. TRANXITION: Objectives And Study Design  Objectives:  To assess the efficacy, safety and tolerability of switching HIV-1 infected patients from NVP IR to XR vs continued NVP IR  Study design:  Open-label, randomised, parallel group study  Subjects:  Adults with HIV RNA <50 copies/mL  Randomised 2:1 to NVP XR 400 mg qd vs NVP IR 200 mg bid  n=200 vs 100 patients  Stratified by background therapy and CD4+ count  Patients remain on previous background therapy  Treatment duration: 48 weeks Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

63. TRANXITION Study Schema NVP IR 200 mg bid regimen ≥18 wks HIV-RNA <50 copies/mL Randomisation (2:1) NVP XR 400 mg qd + background ARV Continued NVP IR 200 mg bid + background ARV Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

64. TRANXITION: Endpoints  Primary endpoint: sustained treatment response at 24 weeks  Sustained treatment response: viral load <50 copies/mL for two consecutive visits prior to Week 24  Secondary endpoints:  Virologic response after 48 weeks of treatment  Proportion of patients with viral load <50 copies/mL at each visit  Change in CD4+ cell count from baseline at each visit  Genotypic resistance associated with virologic failure  Incidence of AIDS progression or death Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

65. Conclusions: Nevirapine Tomorrow  It remains important for health care professionals to have as many evidence-based treatment options for the millions of HIV infected patients worldwide  Once-daily regimens may make it easier for patients to accept and adhere to therapy  Nevirapine XR qd provides the potential for:  Dosing symmetry with preferred combination nucleoside analogues  A more convenient treatment regimen for patients compared with bid dosing Nevirapine is not currently indicated for qd dosing in Europe.

66. Defining success in HIV treatment: should we broaden the parameters? Vicente Soriano Infectious Diseases Department Hospital Carlos III Madrid, Spain

67. Disclosures  Received funding and/or honoraria from most major pharmaceutical companies working in virology

68. Background  Although NNRTIs as a class have been available for over 15 years, new data continue to emerge on older (NVP and EFV) as well as newer agents (ETV)  Although current ARV regimens allow suppression of viral load (HIV-RNA <50 copies/mL) in most adherent individuals, there is still room to improve efficacy –Consideration of new parameters may help in this task

69. New parameters of interest  What is the potential significance of ultra-sensitive viral load measurement?  What is the clinical value of baseline tropism assessment?  What is the clinical relevance of Vitamin D levels in HIV-infected patients?

70. New parameters of interest  What is the potential significance of ultra-sensitive viral load measurement?  What is the clinical value of baseline tropism assessment?  What is the clinical relevance of Vitamin D levels in HIV-infected patients?

71. Ultra-sensitive VL measurement  Residual HIV replication is a major obstacle for HIV eradication using ARV drugs  Low-level HIV replication may contribute to systemic inflammation and drives organ dysfunction in the long-term  Selection of drug resistance has been described in patients with undetectable plasma viremia but low-level replication in other compartments  Encephalitis and meningoencephalitis have been reported in patients treated with ARVs with low CNS penetration

72.  154 HIV-infected patients on ARV therapy with plasma HIV-RNA <50 copies/mL (average: 29 months)  Mean nadir CD4 count 270 cells/µL  NVP was the only independent predictor of VL <2.5 copies/mL  NVP shows a greater penetration into extravascular compartments Plasma HIV-RNA <2.5 copies/mL % patients

73. AIDS 2011; 25: 341-344  165 pts with plasma HIV-RNA 6 months on TDF/FTC + NVP or EFV  HIV-RNA 1–49 c/mL was independently associated with: –EFV vs NVP (OR 2.9; p=0.005) –Shorter length of viral suppression (OR 2.3; p=0.004)  Good penetration of NVP in anatomic compartments could explain greater control of viral replication Plasma HIV-RNA <1 cop/mL % patients p<0.001

74. Two patients with undetectable plasma viremia on atazanavir/r developed encephalitis with detectable viremia in CSF and drug-resistant viruses Three patients with undetectable plasma viremia using ARVs with low CNS penetration (TDF, NFV, LPV/r) developed meningo-encephalitis

75. CNS penetration-effectiveness ranks 4321 NRTIsZidovudineAbacavirDidanosineTenofovir EmtricitabineLamivudineZalcitabine Stavudine NNRTIsNevirapineDelavirdineEtravirine Efavirenz ProteaseIndinavir-rDarunavir-rAtazanavirNelfinavir inhibitorsFosamprenavir-rAtazanavir-rRitonavir IndinavirFosamprenavirSaquinavir Lopinavir-rSaquinavir-r Tipranavir-r Entry-Fusion inhibitors MaravirocEnfuvirtide Integrase inhibitors Raltegravir Letendre et al. 17th CROI 2010; abstract 172 4 = much above average; 1 = below average

76. Sanctuary site penetration-effectiveness ranks CNS 1* Genital tract 2 43211 (>50%)0.5 (10–50%)0 (<10%) NRTIsZDVABCddITDF FTC3TCZDV d4TABC FTC 3TC ddI NNRTIsNVPDLVETR NVP EFV ETR PIsIDV/rDRV/rATZNFVIDV/rAPV/rNFV fAPV/rATZ/rRTVATZ/rRTV IDVfAPVSQVDRV/rLPV/r SQV/r TPV/r Entry/ Fusion inhibitors MVCT-20MVCT-20 Integrase inhibitors RAL 1. Letendre et al. 17th CROI 2010; abstract 172; 2. Lambert-Niclot et al. J Med Virol 2011;83:1391–1394 *Rank: 4 (much above average) to 1 (below average)

77. New parameters of interest  What is the potential significance of ultra-sensitive viral load measurement?  What is the clinical value of baseline tropism assessment?  What is the clinical relevance of Vitamin D levels in HIV-infected patients?

78. The ARTEN study Key data  569 ARV-naive HIV individuals  Non-inferiority of NVP vs ATV/r  Similar CD4 gain with NVP and ATV/r  The combination of NVP + TDF/FTC was effective  Use of CD4 thresholds for NVP initiation was associated with manageable side effects  Better lipid profile following NVP than ATV/r Soriano et al. Antivir Ther 2011;16:339-48. Patients achieving treatment response (%) Treatment response by primary endpoint (ITT) (HIV-RNA <50 copies/mL at 2 visits prior Wk 48) 95% CI= -5.9% to 9.8%; p=0.63 6765 0 20 40 60 80 100 ATZ/rNVP qd + bid Nevirapine is not currently indicated for qd dosing in Europe

79. Tropism sub-study in ARTEN

80. ARTEN Main characteristics of the tropism sub-study population Seclen et al. J Infect Dis 2011;204:139–144 Treatment armHIV tropism ATV/rNVPPR5X4P N146282–33655– Male, %84.287.6>0.188.485.5>0.1 Non-B subtypes, %21.922.7>0.120.810.90.099 HCV coinfection, %11.010.3>0.111.09.1>0.1 Median baseline plasma HIV RNA level, log copies/mL (IQR) 5.19 (4.71–5.61) 5.17 (4.73–5.59) >0.1 5.16 (4.67–5.59) 5.38 (5.03–5.69) 0.044 Median baseline CD4, cells/µL (IQR) 180184>0.1188145<0.001

81. Endpoint, week HIV tropismTreatment arm R5X4PATV/rNVPP Median CD4, cells/µL (IQR) 24 116 (56–197) 117 (66–172) >0.1 116 (72–204) 111 (45–189) >0.1 48 156 (83–244) 180 (86–235) >0.1 180 (99–251) 152 (78–230) 0.037 HIV RNA <50 copies/mL (% patients) 2483.260.90.00177.282.1>0.1 4891.676.90.00988.592.0>0.1 ARTEN Virologic and immunologic outcomes Seclen et al. J Infect Dis 2011;204:139–144

82. ARTEN Predictors of VL response and CD4 recovery Seclen et al. J Infect Dis 2011;204:139–144 End-point, covariableβ Coefficient (95% CI)P CD4 count, cells/µL Week 24Viral tropism (R5)->0.1 Baseline CD4 cell count-14.73 (-27.50 to -1.96)0.024 Baseline viral load33.74 (14.44–53.04)0.001 Week 48Viral tropism (R5)->0.1 Treatment arm (ATV/r)35.05 (7.82–62.27)0.012 Baseline viral load47.86 (27.14–68.58)<0.001 Viral load of <50 copies/mLOR (95% CI) Week 24Baseline CD4 cell count1.40 (0.99–1.96)0.055 Viral tropism (R5)2.62 (1.24–5.52)0.012 Baseline viral load0.19 (0.10–0.36)<0.001 Week 48Viral tropism (R5)2.43 (0.96–6.16)0.061 Viral subtype (non-B subtypes) 0.43 (0.18–1.01)0.054 Baseline CD4 cell count1.68 (1.04–2.72)0.035 Baseline viral load0.41 (0.20–0.84)0.014

83. ARTEN Predictors of VL response and CD4 recovery in HIV clade B viruses (n=315) Seclen et al. J Infect Dis 2011;204:139–144 End-point, covariableβ Coefficient (95% CI)P CD4 cell count, cells/µL Week 24Viral tropism (R5)->0.1 Baseline CD4 cell count-18.34 (-32.14 to -4.53)0.009 Baseline viral load36.68 (14.54–58.83)0.001 Week 48Viral tropism (R5)->0.1 Treatment arm (ATV/r)32.24 (1.33–63.15)0.041 Baseline viral load55.55 (31.30–79.81)<0.001 Viral load of <50 copies/mLOR (95% CI) Week 24Viral tropism (R5)3.50 (1.61–7.64)0.002 Baseline viral load0.17 (0.08–0.34)<0.001 Week 48Viral tropism (R5)4.02 (1.48–10.96)0.007 Baseline viral load0.22 (0.09–0.56)0.001

84. HIV tropism in ARTEN Summary  In ARV-naive patients beginning ART, baseline HIV-1 tropism is an independent predictor of viral load response  Baseline tropism testing should be considered along with viral load, CD4 count and resistance testing in all newly diagnosed HIV individuals  Potential implications for interpretation of clinical trials comparing drug regimens

85. New parameters of interest  What is the potential significance of ultra-sensitive viral load measurement?  What is the clinical value of baseline tropism assessment?  What is the clinical relevance of Vitamin D levels in HIV-infected patients?

86. Vitamin D metabolism Skin Small intestine Liver Kidney 7-dehydro-D Vit D 3 Vit D 25(OH)D (calcidiol) 1,25(OH) 2 D 3 (calcitriol) Vit D 2 (ergocalciferol) Vit D 3 (cholecalciferol)

87.  Screening for Vit D deficiency is recommended only in patients at risk  Measurement of serum 25(OH)D is the best parameter to evaluate Vit D status  Vit D deficiency definition: –Serum 25(OH)D <20 ng/mL (50 nmol/L)  Oral treatment with Vit D2 or D3 supplements (up to 10,000 IU/day) should be considered for individuals with serum 25(OH)D deficiency  Intake of 1500–2000 IU/day Vit D are required to keep serum 25(OH)D >30 ng/mL

88. Diseases associated with Vitamin D deficiency  Type 2 diabetes mellitus  Cardiovascular disease  Chronic hepatitis C  HIV infection

89. Vitamin D levels in HIV-infected adults in NYC  274 HIV-infected adults  25(OH)D levels by RIA  Multivariate analysis for Vit D deficiency:  Black race: OR 4.1; p=0.007  Detectable HIV-RNA: OR 2.4, p=0.024 Kim et al. ARHR (in press) 25(OH)D (nmol/L) % patients

90. Determinants of Vitamin D insufficiency  Reduced milk consumption  Decreased sun exposure (sunscreen use)  Obesity  Others: fat malabsorption syndromes, nephrotic syndrome, primary hyperparathyroidism, anticonvulsants, ARV drugs (efavirenz, tenofovir, PI/r) Holick M et al. J Clin Endocrin Metab 2011 (in press) Gharakhanian & Kotler. AIDS 2011; 25: 531-3.

91. 2 Risk factors for severe vitamin D deficiency [25(OH)D <10µg/L; <25 nmol/L] in 843 HIV-infected patients on cART Exposure to EFV but not NVP associated with severe Vitamin D deficiency Welz et al. AIDS 2010;24:1923–1928 Risk factorUnivariate analysisMultivariate analysis OR (95% CI)P P Black ethnicity2.7 (2.0–3.7)<0.0012.7 (2.0–3.7)<0.001 Female sex1.4 (1.04–1.8)0.031.1 (0.8–1.5)NS Winter season2.2 (1.6–2.9)<0.0012.1 (1.6–2.9)<0.001 CD4 nadir <200 cells/µL1.5 (1.1–2.0)0.011.4 (1.0–1.9)0.05 Current EFV use1.9 (1.4–2.5)<0.0012.0 (1.5–2.7)<0.001 Current NVP use0.7 (0.6–1.0)0.060.6 (2.3–4.1)NS Current PI use0.7 (0.5–0.9)0.010.9 (0.6–1.3)NS Current TDF use0.8 (0.6–1.0)<0.10.8 (0.6–1.1)NS

92. SUN study  70% prevalence of Vit D insufficiency/deficiency (<30 ng/ml) in a cohort of 672 HIV+ patients in the US  Comparison: 79% in US adults from the NHANES database  Predictors of Vit D insufficiency/deficiency: –Non-Caucasian race –High BMI –Decreased UV exposure –Efavirenz  Efavirenz reduces ̴ 5 ng/mL 25(OH)D by inducing 24-hydroxylase, that catabolizes 25(OH)D and 1,25(OH)D Dao et al. Clin Infect Dis2011; 52: 395-404

93. Vit D deficiency & HIV infection Summary  The prevalence of Vit D deficiency/insufficiency is high in HIV+ subjects in the US and West Europe ( ̴ 70%)  Besides classical predictors of low Vit D levels, as reduced sun exposure, obesity and black race, the use of efavirenz is a consistent risk factor for Vit D deficiency  The long-term consequences of low Vit D levels must be assessed, including effects on the immune system and skeletal fragility

94. Defining success in HIV treatment: should we broaden the parameters? Discussion and debate

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