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

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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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HIV Pharmacotherapy

HAART• Highly

• Active

• Anti-

• Retroviral

• Therapy

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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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HIV Life Cycle & Drugs

http://www.globalhealthforum.org

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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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Integrase Inhibitors(INSTI = integrase strand

transfer inhibitor)

raltegravir (RAL) (Isentress)

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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 +


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)


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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


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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


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


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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


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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


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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


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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


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


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


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


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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


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Vicriviroc (VCV) (Phase 3)

CCR5 InhibitorIndication:

Not FDA approved

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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


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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


Results – Day 14


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


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


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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


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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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Questions?

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

Documents

cd4 slide

hiv drugs

hiv life cycle drugs

hiv virus

use of entry inhibitors

nucleotide analogue

integrase inhibitors

nd generation nnrtis