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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
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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
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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
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HAART Drug ClassesNucleoside Reverse
Transcriptase Inhibitors (NRTIs)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease Inhibitors (PIs)Integrase Inhibitors Entry Inhibitors
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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
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Nonnucleoside Reverse Transcriptase Inhibitors efavirenz (EFV) (Sustiva) nevirapine (NVP) (Viramune) etravirine (ETV) (Intelence)*
* 2nd generation
NNRTIs
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Protease Inhibitors (PIs)ritonavir (RTV) (Norvir)
“Boosts” all PIs except nelfinaviratazanavir (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)
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Entry Inhibitors• Fusion Inhibitors
enfuvirtide (T-20) (Fuzeon)• CCR5 Inhibitor
maraviroc (MVC) (Selzentry)
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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
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 count Recommendation
CD4 Count•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)
Treat all
CD4 count >500 cells/mm3 (B/C-III)& do not meet any of the specific conditions listed above
Panel decision was split 50/50
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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
Guidelines can be found onlinehttp://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
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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
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Role of Genotyping in HAARTViral Resistance
• Primary or “acquired”• Secondary
Genotypic/Phenotypic testing
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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
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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
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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
Introduction to Entry Inhibitors
http://scienceblogs.com/denialism/2008/10/exciting_news_on_the_hiv_front.php
A lock, a key, and a turn!
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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
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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
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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.
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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.
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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.
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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.
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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
& tolerabilityViral load reductions from baselineCD4 cell count changes from baselineGenotype, phenotype, & tropism changes
at treatment failure
MERIT Trial
Cooper, et al. J Infect Dis. 2010;201(6):803-813.
Study endpoints
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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 pointnon-inferiority was met
MERIT Trial
Cooper, et al. J Infect Dis. 2010;201(6):803-813.
Results
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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
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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.
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Relevant difference from maraviroc:
Half-life: 28-33 hours
= Once daily dosing!
Vicriviroc (Phase 3)
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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.
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Study designDouble-blind, randomized, & placebo-controlled
48-week studyTreatment 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.
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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.
Results – Day 14
Landovitz RJ, et al. JID 2008;198(8):1113-22.
Treatment GroupsResponse Pbo/EVF
(n=24)25mg (n=23)
50mg (n=22)
75mg (n=23)
HIV-1 RNA level
mean change from baseline (log10 copies/mL)
-0.07 -0.93* -1.18* -1.34*
CD4 cell countmean change from baseline (cells/mm3) +3 +24 +85* +90*
*p<0.05
Results – Week 24
Landovitz RJ, et al. JID 2008;198(8):1113-22.
Treatment GroupsResponse Pbo/EVF
(n=24)25mg (n=23)
50mg (n=22)
75mg (n=23)
HIV-1 RNA level
mean change from baseline, (log10 copies/mL)
-3.2 -2.43* -2.93 -2.65*
CD4 cell countmean change from baseline (cells/mm3) +102 +73 +110 +158
*p<0.05
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 0 9 (39)* 2 (9) 3 (13)
Never achieved <50 copies/mL
0 8 (62) 2 (22) 2 (50)
% refers to the percent randomized to that dose
*P value <0.001, remainder NS
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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.
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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.
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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
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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
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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
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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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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
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