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VIEWS: 15 PAGES: 52

									HIV Drugs, Updates,
   & the Hope for
  Entry Inhibitors

          Kent Williams
 Doctor of Pharmacy Candidate 2011
Wingate University School of Pharmacy
     Saturday, February 19, 2011
                                    1
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.




                                                               2
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




                                                           3
HIV Pharmacotherapy

       HAART
        • Highly
        • Active
        • Anti-
        • Retroviral
        • Therapy
                       4
HAART Drug Classes
        Nucleoside Reverse
            Transcriptase
            Inhibitors (NRTIs)
        Non-Nucleoside Reverse
            Transcriptase
            Inhibitors (NNRTIs)
        Protease Inhibitors (PIs)
        Integrase Inhibitors
        Entry Inhibitors
                                     5
HIV Life Cycle & Drugs




                                            6
         http://www.globalhealthforum.org
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      7
HIV Life Cycle & Drugs




                                            8
         http://www.globalhealthforum.org
NNRTIs
         Nonnucleoside Reverse
          Transcriptase Inhibitors
              efavirenz (EFV) (Sustiva)
              nevirapine (NVP) (Viramune)
              etravirine (ETV) (Intelence)*
                         * 2nd generation

                                               9
HIV Life Cycle & Drugs




                                            10
         http://www.globalhealthforum.org
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)
                                            11
HIV Life Cycle & Drugs




                                            12
         http://www.globalhealthforum.org
Integrase Inhibitors
 (INSTI = integrase strand
   transfer inhibitor)

 raltegravir (RAL) (Isentress)




                              13
HIV Life Cycle & Drugs




                                            14
         http://www.globalhealthforum.org
Entry Inhibitors
 • Fusion Inhibitors
    enfuvirtide (T-20) (Fuzeon)
 • CCR5 Inhibitor
    maraviroc (MVC) (Selzentry)




                                   15
HIV Life Cycle & Drugs




         http://www.globalhealthforum.org
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



                                               17
     When to Initiate HAART Therapy
Clinical Condition and/or CD4 count                                         Recommendation

CD4 Count                                                                  Treat all
     •Consider < 500 cells/mm3 (A/BII)
     •Recommended < 350 cells/mm3 (AI)
     •History of an AIDS-defining illness (CD4 count <200
     cells/mm3) (AI)
Regardless of CD4 count if:
          •Pregnant (AI)
          •HIV-associated nephropathy (AII)
          •Hepatitis B virus (HBV) coinfection (AIII)

CD4 count >500 cells/mm3 (B/C-III)                                          Panel decision
& do not meet any of the specific conditions listed above                   was split 50/50

2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
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

                                                       19
Combination Therapy (HAART):
Preferred Regimens
                      2 NRTIs +


   1 NNRTI
    efavirenz
                               1 PI                         1 INSTI
                    (preferably boosted
                       with ritonavir)


            2011 Guidelines for the Use of Antiretroviral Agents in HIV-1-   20
            Infected Adults and Adolescents
Role of Genotyping in HAART
            Viral Resistance
              • Primary or “acquired”
              • Secondary


            Genotypic/Phenotypic
             testing

                                    21
2011 Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents
           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)
                                                              22
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                              23
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                              24
Introduction to Entry Inhibitors
    A lock, a key, and a turn!




                          http://scienceblogs.com/denialism/2008/10/exciting_news_on_the_hiv_front.php
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   26
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                              27
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.
                                                            28
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




                                                             29
         Cooper, et al. J Infect Dis. 2010;201(6):803-813.
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




                                                             30
         Cooper, et al. J Infect Dis. 2010;201(6):803-813.
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


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



                                                           32
       Cooper, et al. J Infect Dis. 2010;201(6):803-813.
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

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




                                                           34
       Cooper, et al. J Infect Dis. 2010;201(6):803-813.
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.   35
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


                                                                36
          Cooper, et al. J Infect Dis. 2010;201(6):803-813.
Vicriviroc (VCV) (Phase 3)
      CCR5 Inhibitor
      Indication:
        Not FDA approved


                             37
Vicriviroc (Phase 3)
      Relevant difference from
       maraviroc:
        Half-life: 28-33 hours
               = Once  daily
                   dosing!
                                  38
 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.   39
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.   40
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.   41
    Results – Day 14
                                                     Treatment Groups
Response                                   Pbo/EVF       25mg        50mg       75mg
                                           (n=24)       (n=23)      (n=22)     (n=23)
HIV-1 RNA level
mean change from baseline (log10             -0.07       -0.93*     -1.18*     -1.34*
copies/mL)
CD4 cell count
mean change from baseline (cells/mm3)         +3          +24        +85*      +90*




       *p<0.05
                               Landovitz RJ, et al. JID 2008;198(8):1113-22.
    Results – Week 24
                                                     Treatment Groups
Response                                   Pbo/EVF       25mg        50mg      75mg
                                           (n=24)       (n=23)      (n=22)    (n=23)
HIV-1 RNA level
mean change from baseline,                   -3.2       -2.43*      -2.93     -2.65*
(log10 copies/mL)
CD4 cell count
mean change from baseline (cells/mm3)        +102        +73        +110      +158




      *p<0.05
                              Landovitz RJ, et al. JID 2008;198(8):1113-22.
    Results
                                            Treatment Groups
                                  Pbo    25mg              50mg            75mg
                                 /EVF    (n=23)            (n=23)          (n=30)
Virologic Failure               (n=24)
    On or after week 20
As defined by HIV-1 RNA
   level
   ≥400 copies/mL                  0     9 (39)*           2 (9)           3 (13)


   Never achieved <50              0     8 (62)            2 (22)          2 (50)
   copies/mL

% refers to the percent randomized to that dose


*P value <0.001,
    remainder NS               Adapted from: Landovitz RJ, et al. JID 2008;198(8):1113-22.
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.   45
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.   46
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-   47
          idUSN2017965820100120?type=marketsNews
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


                                            48
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


                                                49
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



                                                           50
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                                                       51
Questions?




             52

								
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