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HIV Drugs, Updates, & the Hope for Entry Inhibitors Kent Williams

HIV Drugs, Updates, & the Hope for Entry Inhibitors Kent Williams Doctor of Pharmacy Candidate 2011 Wingate University School of Pharmacy Saturday, February 19, 2011. Disclosures. I have no conflicts of interest in regard to this program.

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HIV Drugs, Updates, & the Hope for Entry Inhibitors Kent Williams

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  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. Disclosures • 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.

  3. Learning Objectives • Introduce 2011 updates in HIV pharmacotherapy • Differentiate recommendations for HIV pharmacotherapy from the 2009Guidelines 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. HIV Pharmacotherapy • HAART • Highly • Active • Anti- • Retroviral • Therapy

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

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

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

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

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

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

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

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

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

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

  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

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

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

  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. 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. 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 A lock, a key, and a turn! http://scienceblogs.com/denialism/2008/10/exciting_news_on_the_hiv_front.php

  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. 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. MERIT Trial 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

  29. MERIT Trial Study design • 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

  30. MERIT Trial Study design • 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

  31. MERIT Trial • 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

  32. MERIT Trial Study endpoints • 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

  33. MERIT Trial Results • 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 Cooper, et al. J Infect Dis. 2010;201(6):803-813.

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

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

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

  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. 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. 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 *p<0.05 Landovitz RJ, et al. JID 2008;198(8):1113-22.

  43. Results – Week 24 *p<0.05 Landovitz RJ, et al. JID 2008;198(8):1113-22.

  44. Results *P value <0.001, remainder NS Adapted from: Landovitz RJ, et al. JID 2008;198(8):1113-22.

  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. 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. 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. 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. 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. 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

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