1. 1 HIV Drugs, Updates, & the Hope for Entry Inhibitors Kent Williams Doctor of Pharmacy Candidate 2011 Wingate University School of Pharmacy Saturday, February 19, 2011

2. 2  I have no conflicts of interest in regard to this program.  I have not received any grant/research support.  I am not a consultant or on a speaker’s bureau.  I am not a stockholder in any drug company. Disclosures

3. 3 Learning Objectives  Introduce 2011 updates in HIV pharmacotherapy  Differentiate recommendations for HIV pharmacotherapy from the 2009 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents  Identify how the mechanism of action of entry inhibitors is unique with regard to the life cycle of the HIV virus  Discuss literature surrounding the use of entry inhibitors

4. 4 HIV Pharmacotherapy  HAART H ighly A ctive A nti- R etroviral T herapy

5. 5 HAART Drug Classes  Nucleoside Reverse Transcriptase Inhibitors (NRTIs)  Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)  Protease Inhibitors (PIs)  Integrase Inhibitors  Entry Inhibitors

6. 6 HIV Life Cycle & Drugs http://www.globalhealthforum.org

7. 7 Drug Classes  Nucleoside Reverse Transcriptase Inhibitors (NRTIs)  zidovudine (AZT, ZDV) ( Retrovir)  lamivudine (3TC) ( Epivir)  emtricitabine (FTC) ( Emtriva)  stavudine (d4T) ( Zerit)  didanosine (ddI) ( Videx EC)  abacavir (ABC) ( Ziagen)  tenofovir (TDF) – ( Viread)* * NucleoTide analogue

8. 8 HIV Life Cycle & Drugs http://www.globalhealthforum.org

9. 9  Nonnucleoside Reverse Transcriptase Inhibitors  efavirenz (EFV) ( Sustiva)  nevirapine (NVP) ( Viramune)  etravirine (ETV) ( Intelence) * * 2 nd generation NNRTIs

10. 10 HIV Life Cycle & Drugs http://www.globalhealthforum.org

11. 11  Protease Inhibitors (PIs)  ritonavir (RTV) ( Norvir)  “Boosts” all PIs except nelfinavir  atazanavir (ATV) ( Reyataz)  darunavir (DNV) (Prezista)  lopinavir/ritonavir (LPV/r) (Kaletra)  fosamprenavir (FPV) ( Lexiva)  indinavir (IDV) (Crixivan)  nelfinavir (NFV) (Viracept)  saquinavir (SQV) (Invirase)  tipranavir (TPV) (Aptivus)

12. 12 HIV Life Cycle & Drugs http://www.globalhealthforum.org

13. 13  Integrase Inhibitors (INSTI = integrase strand transfer inhibitor)  raltegravir (RAL) (Isentress)

14. 14 HIV Life Cycle & Drugs http://www.globalhealthforum.org

15. 15  Entry Inhibitors Fusion Inhibitors  enfuvirtide (T-20) (Fuzeon) CCR5 Inhibitor  maraviroc (MVC) (Selzentry)

16. HIV Life Cycle & Drugs http://www.globalhealthforum.org

17. 17 HAART - Monitoring  Viral Load: (“Plasma HIV RNA”) measure of viral replication & CD4 destruction  CD4 T cell counts : measure of extent of immune system damage ( AI )  % T cells that are CD4

18. When to Initiate HAART Therapy 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Clinical Condition and/or CD4 countRecommendation  CD4 Count Consider < 500 cells/mm 3 ( A/BII ) Recommended < 350 cells/mm 3 ( AI ) History of an AIDS-defining illness (CD4 count <200 cells/mm 3 ) ( AI )  Regardless of CD4 count if: Pregnant ( AI ) HIV-associated nephropathy ( AII ) Hepatitis B virus (HBV) coinfection ( AIII ) Treat all CD4 count >500 cells/mm 3 ( B/C-III ) & do not meet any of the specific conditions listed above Panel decision was split 50/50

19. 19 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents  Guidelines can be found online http://aidsinfo.nih.gov U.S. Dept. of Health & Human Services (DHHS)  USUALLY come out every year -2009 December -2010 – May Perinatal -2011 January  Guidelines for HIV-1

20. 20 2 NRTIs + 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents Combination Therapy (HAART): Preferred Regimens 1 NNRTI efavirenz 1 PI (preferably boosted with ritonavir) 1 INSTI

21. 21 Role of Genotyping in HAART  Viral Resistance Primary or “acquired” Secondary Genotypic/Phenotypic testing

22. 22 NNRTI-based Regimen EFV + TDF/FTC [tenofovir/emtricitabine](Truvada) All 3 = Atripla ( AI ) PI-based Regimens ATV/r + TDF/FTC (Truvada) ( AI ) DRV/r + TDF/FTC (Truvada) ( AI ) INSTI-based Regimen RAL + TDF/FTC (Truvada) ( AI ) Pregnant Women HAART including LPV/r BID (Kaletra) + ZDV(AZT) or 3TC (lamivudine) ( AI ) 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

23. 23 New for 2011 “Acceptable” Regimens: CCR5 Antagonist-Based Regimens -2 NRTIs + Entry Inhibitor (CCR5) -Based on MERIT study - Requires tropism assays 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents

24. 24 What is a “Tropism”?  Defined by:  Virus type (R5, X4, or X4R5)  CD4 Chemokine coreceptors (CCR5 or CXCR4, or both)  PICTURE OF DOORS before this slide  Duplex 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents

25. Introduction to Entry Inhibitors http://scienceblogs.com/denialism/2008/10/exciting_news_on_the_hiv_front.php A lock, a key, and a turn!

26. 26 Maraviroc (Selzentry) (MRC)  Approved August 2007  Inhibits R5 coreceptors  CYP3A substrate  Toxicities:  Black box warning: Hepatotoxicity  Half-life 14-18 hours = Twice daily dosing Lexi-Comp, Inc.. Hudson, OH: 2010

27. 27 Maraviroc (Selzentry) (MRC)  2011 “Acceptable” regimen  MVC + ZDV/3TC (CI)  MVC + TDF/FTC or ABC/3TC (CIII)  Approved for use in ART- naïve patients as an “acceptable” regimen 2011 Guidelines for the Use of Antiretroviral Agents in HIV-1- Infected Adults and Adolescents

28. 28 Phase IIb/III Maraviroc versus Efavirenz, both in combination with zidovudine- lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection MERIT Trial Cooper, et al. J Infect Dis. 2010;201(6):803-813.

29. 29  Randomized, double-blind, double-dummy, non-inferiority  16 week interim – evaluate MVC arms for noninferiority  48 week primary – April 2007 final data collected  96 week total – blinded until June 2011 MERIT Trial Study design Cooper, et al. J Infect Dis. 2010;201(6):803-813.

30. 30  Patient allocation  917 subjects assigned to zidovudine/lamivudine (300 mg/150 mg twice daily) + :  efavirenz 600 mg once daily  or maraviroc 300 mg once daily  or maraviroc 300 mg twice daily MERIT Trial Study design Cooper, et al. J Infect Dis. 2010;201(6):803-813.

31. 31  Inclusion  Men, non-pregnant women > age 16  HIV-1 RNA viral load of > 2,000 copies/mL  Exclusion  Resistance to zidovudine, lamivudine, or efavirenz  Opportunistic infections  Treatment-experienced  Pregnancy or planned pregnancy during the trial  X4- or dual/mixed-tropic virus or repeated assay failure MERIT Trial Cooper, et al. J Infect Dis. 2010;201(6):803-813.

32. 32  Primary:  Proportion of patients with undetectable viral load (<50 HIV-1 RNA copies/mL) at 48 weeks  Proportion of patients with virologic failure (<400 HIV-1 RNA copies/mL) at 48 weeks  Secondary:  Comparing treatment regimens for safety & tolerability  Viral load reductions from baseline  CD4 cell count changes from baseline  Genotype, phenotype, & tropism changes at treatment failure MERIT Trial Cooper, et al. J Infect Dis. 2010;201(6):803-813. Study endpoints

33. 33  Enrolled 917 patients, treated 895 patients  Baseline characteristics were similar  Interim analysis:  Stopped MRC once daily arm for not meeting thresholds for noninferiority  Primary analysis:  <50 copies/mL co-end point  To meet non-inferiority margin < -10%  was -10.9%, non-inferiority was NOT met  <400 copies/mL co-end point  non-inferiority was met MERIT Trial Cooper, et al. J Infect Dis. 2010;201(6):803-813. Results

34. 34  Post hoc re-analysis - ruled out any results from patients carrying non-R5 type virus (X4).  Non-inferiority was met for both coprimary endpoints MERIT Trial Cooper, et al. J Infect Dis. 2010;201(6):803-813. Results

35. 35 Adverse Effects Noted  maraviroc arm  bronchitis & nasopharyngitis were most common (incidence >2%)  efavirenz arm  Diarrhea, vomiting, dizziness, abnormal dreams, cough, and rash Cooper, et al. J Infect Dis. 2010;201(6):803-813.

36. 36 Trial Conclusions  Authors’ conclusions: In treatment naïve with R5 virus, maraviroc combos provided… –Better CD4 count increases –Lower rate of AEs –Lower rate of virologic response *due to presence of X4 virus  Additional thoughts: –Noninferiority shown –Favorable Adverse effect profile –Maraviroc combinations provide a viable option for therapy Cooper, et al. J Infect Dis. 2010;201(6):803-813.

37. 37 Vicriviroc (VCV) (Phase 3)  CCR5 Inhibitor  Indication: Not FDA approved

38. 38  Relevant difference from maraviroc:  Half-life: 28-33 hours = Once daily dosing! Vicriviroc (Phase 3)

39. 39 Phase II Study of Vicriviroc versus Efavirenz (both with Zidovudine/Lamivudine) in Treatment-Naïve Subjects with HIV-1 Infection Landovitz RJ, et al. JID 2008;198(8):1113-22.

40. 40 Study design  Double-blind, randomized, & placebo-controlled 48-week study  Treatment groups:  Vicriviroc 25mg, 50mg, 75mg, or Placebo PO once daily X 14 days  At day 14, all subjects added lamivudine/zidovudine PO twice daily X 46 weeks  At day 14, the placebo arm added open- label efavirenz PO 600mg daily X 46 weeks Landovitz RJ, et al. JID 2008;198(8):1113-22.

41. 41 Study endpoints  Primary:  Mean change in HIV-1 RNA load from baseline to day 14  Secondary:  Mean change in:  CD4 cell count from baseline to day 14  HIV-1 RNA load and CD4 cell count from baseline to week 24  Virologic failure  Tropism changes Landovitz RJ, et al. JID 2008;198(8):1113-22.

42. Results – Day 14 Landovitz RJ, et al. JID 2008;198(8):1113-22. Treatment Groups Response Pbo/EVF (n=24) 25mg (n=23) 50mg (n=22) 75mg (n=23) HIV-1 RNA level mean change from baseline (log 10 copies/mL) -0.07-0.93*-1.18*-1.34* CD4 cell count mean change from baseline (cells/mm 3 )+3+24+85*+90* *p<0.05

43. Results – Week 24 Landovitz RJ, et al. JID 2008;198(8):1113-22. Treatment Groups Response Pbo/EVF (n=24) 25mg (n=23) 50mg (n=22) 75mg (n=23) HIV-1 RNA level mean change from baseline, (log 10 copies/mL) -3.2-2.43*-2.93-2.65 * CD4 cell count mean change from baseline (cells/mm 3 )+102+73+110+158 *p<0.05

44. Results Adapted from: Landovitz RJ, et al. JID 2008;198(8):1113-22. Treatment Groups Virologic Failure Pbo /EVF (n=24) 25mg (n=23) 50mg (n=23) 75mg (n=30) On or after week 20 As defined by HIV-1 RNA level ≥400 copies/mL 09 (39)*2 (9)3 (13) Never achieved <50 copies/mL 08 (62)2 (22)2 (50) % refers to the percent randomized to that dose *P value <0.001, remainder NS

45. 45 Coreceptor Changes  8 subjects experienced tropism change  7 Dual/Mixed (DM)  1 confirmed X4 3 placebo (No vicriviroc exposure)  6 of 8 were detected on or before day 14, including the confirmed X4 Landovitz RJ, et al. JID 2008;198(8):1113-22.

46. 46 Trial Conclusions  At the doses studied, VCV  produces antiviral activity  dose related ↑ in CD4 cell count  safe & well tolerated  Compared to 2 NRTIs + efavirenz, 2 NRTIs + Vicriviroc = increased rates of virologic failure at doses of 25, 50, & 75mg  Study of higher doses with combination therapy is warranted Landovitz RJ, et al. JID 2008;198(8):1113-22.

47. 47 Latest on Vicriviroc Still in phase III trials Testing in treatment-naïve patients Merck will not seek FDA approval “at this time.” Reuters online 1-20-10 http://www.reuters.com/article/2010/01/20/merck-hiv- idUSN2017965820100120?type=marketsNews

48. 48 Conclusion  No major updates in HIV pharmacotherapy except entry inhibitors as “acceptable” combination regimens  Monitor CD4 counts, viral load (HIV RNA), and tropism if considering chemokine receptor inhibitors

49. 49 Conclusion  Since approval of maraviroc in 2007, CCR5 antagonists provide a novel MOA inhibiting viral entry into healthy CD4 T-cells  Entry inhibitors block entry into cells as opposed to other MOAs of HIV drugs that work WITHIN the cell

50. 50 Conclusion  Drugs that block entry could revolutionize HIV-1 pharmacotherapy  My “HOPE” for entry inhibitors  More sensitive tropism assays  Continue research regarding tropism  Drugs with action against dual tropism  CXCR4 Antagonists, combinations  Optimization of the role of entry inhibitors in combination therapy requires further study

51. 51 References  Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-813.  Landovitz RJ, Angel JB, Hoffmann C, et al; Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis. 2008 Oct 15;198(8):1113-22.  Gulick RM, Su Z, Flexner C, et al; Phase 2 Study of the Safety and Efficacy of Vicriviroc, a CCR5 Inhibitor, in HIV-1-Infected, Treatment-Experienced Patients. JID. 2007 June 5; 196: 304-12  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; 1-174. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 24 Jan 2011  http://scienceblogs.com/denialism/2008/10/exciting_news_on_the_ hiv_front.php  ClinicalTrials.gov  http://s3.images.com/huge.66.330965.JPG  http://www.globalhealthforum.org/why-we-can%E2%80%99t-yet- cure-hiv.php

52. 52 Questions?