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New and Emerging Therapies for the Clinical Management of HIV Infection. Sponsored for CME credit by Rush University Medical Center. Supported by an independent educational grant from Gilead Sciences Medical Affairs. CME Disclaimer, Disclosure Information, and Slide Handouts. CME Disclaimer - PowerPoint PPT Presentation
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New and Emerging Therapies for the Clinical Management of HIV Infection
Sponsored for CME credit by Rush University Medical Center
Supported by an independent educational grant from Gilead Sciences Medical Affairs
2
CME Disclaimer, Disclosure CME Disclaimer, Disclosure Information, and Slide HandoutsInformation, and Slide Handouts
● CME DisclaimerCME Disclaimer- These slides may not be videotaped, published, posted online, and/or presented for
Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications
● Disclosure InformationDisclosure Information- It is the policy of the Rush University Medical Center Office of Continuing Medical Education
to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME
- Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months
- If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content
● Slide HandoutsSlide Handouts- The enclosed slide handouts are provided for reference purposes only
- The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation
3
EducatorEducator
● Disclosures- Grants/Research Support: n/a- Consultant: n/a- Speakers’ Bureau: Gilead, Janssen- Stock Shareholder: n/a- Other Financial or Material Support: n/a
Lisa Hightow-Weidman, MD, MPHAssociate Professor
University of North Carolina at Chapel Hill
4
Accreditation and DesignationAccreditation and Designation
Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this live activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity.
The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-13-043-L02-P). This activity is accredited for 1 hour of continuing pharmacy education (CPE) credit. The University of Florida College of Pharmacy will report all credit to CPE Monitor within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.
Supported by an independent educational grant from Gilead Sciences Medical Affairs.
ANAC is an approved provider of continuing nursing education (CNE) by the Virginia Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is approved for 1.0 contact hour by the Association of Nurses in AIDS Care.
5
FacultyFaculty
CME Course DirectorCME Course DirectorHarold A. Kessler, MDProfessor of Medicine and Immunology/Microbiology
Associate Director,Section of Infectious Diseases
Rush University Medical CenterChicago, Illinois
Content Development and TrainingContent Development and TrainingEric S. Daar, MD
Chief, Division of HIV MedicineHarbor-UCLA Medical Center
Torrance, CaliforniaProfessor of Medicine
David Geffen School of Medicine at UCLALos Angeles, California
CME ReviewerCME ReviewerDavid M. Simon, MD, PhD
Associate ProfessorSection of Infectious Diseases
Rush University Medical CenterChicago, Illinois
CNE ReviewerCNE ReviewerAllison R. Webel, RN, PhD
Instructor and KL2 ClinicalResearch Scholar
Frances Payne Bolton School of NursingCase Western Reserve University
Cleveland, Ohio
6
Faculty DisclosuresFaculty Disclosures
CME Course Director:Harold A. Kessler, MD
Content Development and Training:Eric S. Daar, MD
Grants/research support
None Abbott, Gilead Sciences, Merck, Pfizer, ViiV
Consultant None Bristol-Myers Squibb, Gilead Sciences, Merck, ViiV
Speakers’ bureau None None
Stock shareholder
Abbott Laboratories, GlaxoSmithKline, Merck
None
Other financial or material support
None None
7
Faculty DisclosuresFaculty Disclosures
CME Reviewer:David M. Simon, MD, PhD
CNE Reviewer:Allison R. Webel, RN, PhD
Medical Editor:Peter Pinkowish
Grants/research support
None None None
Consultant None None None
Speakers’ bureau
None None None
Stock shareholder
None None None
Other financial or material support
None None None
8
Opinions and Off-Label DiscussionsOpinions and Off-Label Discussions
The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or
recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, the Association of Nurses in AIDS
Care, or the University of Florida College of Pharmacy
The faculty may have included discussion on unlabeled usesof a commercial product or an investigational use of a
product not yet approved for this purpose
Please consult the full prescribing information before usingPlease consult the full prescribing information before usingany medication mentioned in this programany medication mentioned in this program
9
New Electronic Evaluation ProcessNew Electronic Evaluation Process
● Please clearly print your information on the Sign-in Sheet
● You will receive an electronic evaluation to the email address provided within 1 business day
● Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed
● Completion Is Required for CME/CNE/CPE credit and future attendance
● Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
10
Learning ObjectivesLearning Objectives(CME/CNE and CPE)(CME/CNE and CPE)
● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine and/or advance practice nursing:
- Appropriately select antiretroviral therapy for my HIV-infected patients according to the guideline recommendations by the Department of Health and Human Services
- Counsel my HIV-infected patients on the benefits and risks associated with antiretroviral therapy
- Counsel my HIV-infected patients on new potential drug targets against HIV infection
- Counsel my HIV-infected patients how HIV agents in late-stage clinical development may impact future management of HIV-infected patients
CME/CNECME/CNE● Upon completion of this activity, the
pharmacist should be able to:
- Recommend antiretroviral therapy for my HIV-infected patients according to the guideline recommendations by the Department of Health and Human Services
- Counsel my HIV-infected patients on the benefits and risks associated with antiretroviral therapy
- Counsel my HIV-infected patients on new potential drug targets against HIV infection
- Counsel my HIV-infected patients how HIV agents in late-stage clinical development may impact future management of HIV-infected patients
CPECPE
11
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
12
Worldwide Treatment andPrevention Gaps (2011)
● On ART: 8 million
● Number needing ART: 15 million
● New infections: 2 million
● People were waiting to become treatment-eligible, sicken, or die: ~24 million
● Estimated coverage of ART in low- and middle-income countries: 36%
Granich R, et al. Curr Opin HIV AIDS. 2013;8:41-49.
13
Chronic HIV in the US:Underdiagnosed and Undertreated
Nu
mb
er (
in ‘
000s
)
Prevalence Diagnosed Treated
1,106,400-1,200,000
874,056-960,000
437,028-489,600
~80%Diagnosed
~40%Treated
Smith MK, et al. PLoS One. 2012;9:e1001260.Gardner EM, et al. Clin Infect Dis. 2011;52:793-800.Burns DN, et al. Clin Infect Dis. 2010;51:725-731.
~20% of AllHIV-Infected Are HIV RNA
<50 copies/mL
209,773-376,992
Viral Suppression
14
No Single, Stand-Alone HIV Prevention Intervention Will Halt the HIV Pandemic
● Over the past 30 years, existing prevention strategies have had limited to no success
- Education about risks
- Behavioral interventions to decrease risk
- Harm reduction
- Vaccines
15
The Shift Towards EarlierInitiation of Antiretroviral Therapy
● Newer ART regimens
- Generally better tolerated, more convenient, and more potent than older regimens
● Survival benefit
- Randomized controlled trials
- Observational cohort data
● Untreated HIV
- Maybe associated the development of non-AIDS-defining illness
● Biologic rationale
● Effective ART reduces HIV transmission
16
Simultaneous Use of Different Classes of Prevention Strategies
BiomedicalInterventions
StructuralInterventions
CommunityInterventions
Individual andSmall GroupBehavioral
Interventions
HIV Testing,Linkage to Care,Expanded ART
CoverageCombinationHIV
Prevention
17
FDA Approves First Drug for Reducing the Risk of Sexually Acquired HIV Infection (July 16, 2012)
● Emtricitabine/tenofovir DF
- Indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults at high risk
• Other prevention methods (eg, safe sex practices, risk reduction counseling, and regular HIV testing)
● Revised PrEP Boxed Warning
- Use in those who are confirmed HIV-negative prior to prescribing the drug and at least every 3 months during use
- Contraindicated in those with unknown or positive HIV status
● Gilead Sciences conditions of PrEP approval
- Collect viral isolates from individuals who acquire HIV while taking emtricitabine/tenofovir DF and to evaluate these isolates for the presence of resistance
- Collect pregnancy outcomes data for women who become pregnant while taking emtricitabine/tenofovir DF for PrEP
- Conduct a trial to evaluate drug adherence and its relationship to adverse events, risk of seroconversion, and resistance development in seroconverters
Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm.
18
CDC Interim Guidance: PrEP in Heterosexually Active Adults and MSM
● Interim guidance as part of a comprehensive set of HIV prevention services
● PrEP has the potential to contribute to effective and safe HIV prevention for if it is:
- Targeted to those at high risk for HIV acquisition
- Delivered as part of a comprehensive set of prevention services
• Risk reduction and PrEP adherence counseling
• Ready access to condoms
• Diagnosis and treatment of STIs
- Accompanied by monitoring HIV status, side effects, adherence, and risk behavior
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.
19
● Proof of efficacy study of topical tenofovir gel in women- CAPRISA 004
● First oral PrEP study of emtricitabine/tenofovir DF for MSM- iPrEx
● Proof of efficacy studies in young, heterosexual adults in Africa- Partners PrEP
- TDF2 (CDC4940)
● Early termination due to futility of PrEP in women- FEM-PrEP
- VOICE (oral tenofovir DF and topical tenofovir arms only)
PrEP Trial Results
20
CDC Interim Guidance for HealthcareProviders: Beginning PrEP Medication Regimen
● Prescribe emtricitabine/tenofovir DF (200/300 mg)
- 1 tablet daily
● In general, prescribe no more than a 90-day supply
- Renew only after confirming patient remains HIV uninfected
● If HBV infected
- Consider emtricitabine/tenofovir DF for HBV and HIV prevention
● Provide risk-reduction and PrEP medication adherence counseling and condoms
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.
21
CDC Interim Guidance for HealthcareProviders: Follow-Up While on PrEP
● Evaluate and support PrEP medication adherence at each follow-up visit (more often if needed)
- For women, conduct pregnancy test
● Every 2 to 3 months
- HIV antibody test (document negative result)
- Assess
• Risk behaviors and provide risk-reduction counseling and condoms
• STI symptoms (if present, test and treat as needed)
● Every 6 months
- Test for STI regardless of symptomatology (treat as needed)
● Every 3 months after initiation, then yearly while on PrEP
- Blood urea nitrogen
- Serum creatinine
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.
22
CDC Interim Guidance for HealthcareProviders: Discontinuing PrEP
● Perform HIV test(s) to confirm HIV status
- If positive
• Order and document results of resistance testing
• Establish linkage to care
• For pregnant women, inform prenatal-care provider and coordinate care to maintain HIV prevention during pregnancy and breastfeeding
- If negative
• Establish linkage to risk-reduction support services as indicated
● If active HBV infection at initiation of PrEP
- Consider appropriate medication for continued treatment of HBV infection
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68.CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.
23
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
24
DHHS Guidelines:When To Start Perspectives
● Untreated HIV infection may have detrimental effects at all stages of infection
- Effects of immune deficiency, direct effects of HIV on specific end organs, and the indirect effects of HIV-associated inflammation on these organs
● Earlier treatment may prevent the damage associated with HIV replication during early stages of infection
- Sustaining viral suppression and maintaining higher CD4 count via ART delays or prevents some non-AIDS-defining complications and disorders
● Success of ART hinges on avoiding treatment interruptions
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.
25
When to Start Treatment
Clinical CategoryCD4 Count (cells/mm3)
HIV RNA(copies/mL)
2/2013DHHS
Guidelines
2012IAS-USA
Guidelines
AIDS-defining illness or severe symptoms
Any value Any value Treat
Asymptomatic <500 Any value Treat
>500 Any value Treat
Pregnant women Any value Any value Treat
HIV-associated nephropathy Any value Any value Treat
HIV/HBV coinfection when HBV treatment is indicated
Any value Any value Treat
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308:387-402.
The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.
26
DHHS Guidelines: Preferred Regimens
NNRTI Efavirenz1/emtricitabine2/tenofovir DF3
PI Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI Raltegravir + emtricitabine2/tenofovir DF3
Pregnant women
Lopinavir/r bid + zidovudine/lamivudine2
INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception.2Lamivudine may substitute for emtricitabine or visa versa.3Tenofovir DF should be used with caution in patients with renal insufficiency.4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.
27
DHHS Guidelines: Alternative Regimens
NNRTI Efavirenz + (abacavir1 or zidovudine)/lamivudine2
Rilpivirine3/emtricitabine2/tenofovir DF
Rilpivirine3 + abacavir/lamivudine2
PI Atazanavir + ritonavir + abacavir/lamivudine2
Darunavir + ritonavir + abacavir/lamivudine2
Fosamprenavir + ritonavir (qd or bid) + abacavir/lamivudine2 or emtricitabine2/tenofovir DF
Lopinavir/r4 (qd or bid) + abacavir/lamivudine2 or emtricitabine2/tenofovir DF
INSTI Raltegravir + abacavir/lamivudine2
Elvitegravir/cobicistat/emtricitabine/tenofovir DF5
1Abacavir should not be used in patients who test positive for HLA-B*5701. Use abacavir with caution in patients with high risk of cardiovascular disease or pretreatment HIV RNA >100,000 copies/mL.2Lamivudine may substitute for emtricitabine or visa versa.3Use rilpivirine with caution in patients with pretreatment HIV RNA >100,000 copies/mL.
4Once-daily lopinavir/r is not recommended in pregnant women.5Patients with creatinine clearance >70 mL/min.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.
28
No One Right Option for Everyone:Limitations of Current First-Line Regimens
● Efavirenz-based regimens
- Not recommended for women at risk of becoming pregnant
- CNS toxicity
- Rash
- Low barrier to resistance
● Raltegravir-based regimens
- Twice-daily administration
- Relatively low barrier to resistance
- Lack of second-line integrase inhibitor option
● Ritonavir-boosted PI-based regimens
- Higher pill count
- Gastrointestinal toxicity
29
Simplified and Convenient ART:Achieving Goals of Therapy
● Treatment goals
- Reduce HIV-associated morbidity and prolong the duration and quality of survival
- Restore and preserve immunologic function
- Maximally and durably suppress plasma HIV viral load
- Prevent HIV transmission
● Individualize strategies to achieve goals
- Tailor regimens to enhance adherence
- Pretreatment genotypic resistance testing
- Maximize conditions to promote ART adherence
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.
30
Potential Therapeutic Targets
Reverse Transcriptase
Inhibitors
Protease Inhibitors
FusionInhibitors
CytoplasmCytoplasm
NucleusNucleus
CCR5Inhibitors
Integrase Inhibitors
31
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
32
Study 102: QUAD Versus Efavirenz/Emtricitabine/Tenofovir DF
Phase 3 study(192 weeks)
Treatment-naïveDouble-blind
HIV RNA >5000 copies/mLAny CD4 countNon-inferiority(12% margin)
Sax PE, et al. Lancet. 2012;379:2439-2448.Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
Single-Tablet, Once-Daily Regimens
Randomization1:1
Efavirenz 600 mg/Emtricitabine/Tenofovir DF (n=352)
Elvitegravir 150 mg/Cobicistat 150 mg/Emtricitabine/Tenofovir DF (n=348)
PrimaryEndpointWeek 48
HIV RNA<50 Copies/mL
33
Study 102:Baseline Demographics
Sax PE, et al. Lancet. 2012;379:2439-2448.Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
34
Study 102:Virologic and Immunologic Outcomes
Pat
ien
ts (
%)
HIV RNA <50 Copies/mL CD4 Cell Gain
88%
48(n=348/352)
96(n=348/352)
84%
CD
4 G
ain
(c
ell
s/m
m3 )
239*
295
*P=0.009.
Difference (%):Difference (%):3.6 (-1.6, 8.8)3.6 (-1.6, 8.8)
84% 82%
Difference (%):Difference (%):2.7 (-2.9, 8.3)2.7 (-2.9, 8.3)
206
273
EVG/COBI/FTC/TDF EFV/FTC/TDF
Week
EVG/COBI/FTC/TDF EFV/FTC/TDF
Sax PE, et al. Lancet. 2012;379:2439-2448.Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
48(n=325/315)
96(n=307/302)
Week
35
Study 102: Virologic Outcomesby Baseline HIV RNA
Pat
ien
ts (
%)
Baseline HIV RNA <100K Copies/mL
90%
48(n=348/352)
96(n=230/236)
85% 86%81%
EVG/COBI/FTC/TDF EFV/FTC/TDF
Week
Sax PE, et al. Lancet. 2012;379:2439-2448.Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
Pat
ien
ts (
%)
Baseline HIV RNA >100K Copies/mL
84%
48(n=348/352)
96(n=230/236)
82% 81% 83%
EVG/COBI/FTC/TDF EFV/FTC/TDF
Week
36
Study 102 (Week 96):NNRTI, Integrase, and NRTI Resistance
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
37
Study 102 (Week 96):Safety and Tolerability
Week 96
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
38
Study 103: QUAD VersusAtazanavir/r + Emtricitabine/Tenofovir DF
Phase 3 study(192 weeks)
Treatment-naïveDouble-blind
HIV RNA >5000 copies/mLAny CD4 countNon-inferiority(12% margin)
Randomization1:1
Atazanavir/r +Emtricitabine/Tenofovir DF (n=355)
DeJesus E, et al. Lancet. 2012;379:2429-2438.Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF (n=353)
PrimaryEndpointWeek 48
HIV RNA<50 Copies/mL
Once-Daily Regimens
39
Study 103:Baseline Demographics
DeJesus E, et al. Lancet. 2012;379:2429-2438.Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
40
Study 103:Virologic and Immunologic Outcomes
Pat
ien
ts (
%)
HIV RNA <50 Copies/mL CD4 Cell Gain
90%
48(n=353/355)
96(n=353/355)
87%
CD
4 G
ain
(c
ell
s/m
m3 ) 207
256
Difference (%):Difference (%):2.7 (-2.1, 7.5)2.7 (-2.1, 7.5)
83% 82%
Difference (%):Difference (%):1.1 (-4.5, 6.7)1.1 (-4.5, 6.7)
211
261
EVG/COBI/FTC/TDF ATV/r + FTC/TDF
Week
48(n=334/321)
96(n=316/315)
Week
EVG/COBI/FTC/TDF ATV/r + FTC/TDF
DeJesus E, et al. Lancet. 2012;379:2429-2438.Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
41
Study 103: Virologic Outcomesby Baseline HIV RNA
Pat
ien
ts (
%)
Baseline HIV RNA <100K Copies/mL
93%
48(n=203/214)
96(n=203/214)
90%84% 84%
EVG/COBI/FTC/TDF ATV/r + FTC/TDF
Week
Pat
ien
ts (
%)
Baseline HIV RNA >100K Copies/mL
85%
48(n=150/141)
96(n=150/141)
82% 82% 80%
EVG/COBI/FTC/TDF ATV/r + FTC/TDF
Week
DeJesus E, et al. Lancet. 2012;379:2429-2438.Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
42
Study 103 (Week 96):Resistance
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
43
Study 103 (Week 96):Safety and Tolerability
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
44
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF:Dosing and Safety Considerations
● Meal restrictions
- Take with meal
● Adverse events
- Diarrhea, nausea
• Comparable with ATV/r, usually mild and rarely leads to drug discontinuation
- Early decrease in estimated GFR from cobicistat
• Generally benign if <0.4 mg/dL increase in creatinine
- Drug-drug interactions: may be similar to ritonavir-boosted PI, do not use with other PIs
● Elvitegravir and raltegravir share similar resistance pathways (cross resistant)
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.Johnson VA, et al. Top Antivir Med. 2011;19:156-164.
45
ECHO and THRIVE Studies:Study Design (96 Weeks)
Phase 3 Studies Treatment-naïve, HIV RNA >5000 copies/mL, no NNRTI resistance-associated mutations
Randomization1:1
Efavirenz 600 mg qd +Emtricitabine/Tenofovir DF qd
Primary endpoint: non-inferiority at week 48 (lower confidence interval <12%).Primary endpoint: non-inferiority at week 48 (lower confidence interval <12%).*Investigator*Investigator’’s choice: emtricitabine/tenofovir DF, zidovudine/lamivudine, abacavir/lamivudine.s choice: emtricitabine/tenofovir DF, zidovudine/lamivudine, abacavir/lamivudine.
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].Molina J-M, et al. Lancet. 2011;378:238-246.Cohen CJ, et al. Lancet. 2011;378:229-237.
Rilpivirine 25 mg qd +Emtricitabine/Tenofovir DF qd
ECHO(n=690)
Randomization1:1
Efavirenz 600 mg qd +2 NRTIs
Rilpivirine 25 mg qd +2 NRTIs*
THRIVE(n=678)
46
ECHO and THRIVE Studies:Baseline Demographics
ECHO THRIVE
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].Molina J-M, et al. Lancet. 2011;378:238-246.Cohen CJ, et al. Lancet. 2011;378:229-237.
47
ECHO and THRIVE Studies:HIV RNA <50 Copies/mL(ITT-TLOVR)
Rilpivirine Efavirenz
Pat
ien
ts (
%)
ECHO(n=346/344)
THRIVE(n=340/338)
Pooled Data(n=686/682)
83%
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].Molina J-M, et al. Lancet. 2011;378:238-246.Cohen CJ, et al. Lancet. 2011;378:229-237.
83% 86%82%
78% 78%
Week 48
CD4+196
cells/µL
CD4+182
cells/µL
CD4+189
cells/µL
CD4+171
cells/µL
CD4+228
cells/µL
CD4+219
cells/µL
Week 96
48
Pooled ECHO/THRIVE Post-Hoc Analysis:HIV RNA <50 Copies/mL (Week 96)
0
20
40
60
80
100
HIV
RN
A <
50 C
op
ies/
mL
(%
)
By Baseline HIV RNA(copies/mL)
By Baseline CD4(cells/mm3)
84%
70%
<100K(n=368/329)
Rilpivirine Efavirenz
80%75%
All patients received emtricitabine/tenofovir DF.Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].
>100K(n=318/353)
0
20
40
60
80
100
HIV
RN
A <
50 C
op
ies/
mL
(%
)
56%
71%
<50(n=34/36)
Rilpivirine Efavirenz
69%75%
50-<200(n=194/175)
81% 79%
85%79%
200-<350(n=313/307)
>350(n=144/164)
49
Pooled ECHO/THRIVE (Week 96):Discontinuations and Virologic Failure
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].
50
Pooled ECHO/THRIVE (Week 96):Safety
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].*P<0.0001 and †P=0.0039 versus rilpivirine.
51
ECHO/THRIVE:Conclusions
● Efficacy
- Week 0-48: rilpivirine was non-inferior to efavirenz
- Week 48-96: comparable between rilpivirine and efavirenz arms
- Better rilpivirine response: baseline HIV RNA <100K versus >100K copies/mL
● Overall virologic failure rate
- Week 0-48: higher in the rilpivirine arm
- Weeks 48-96: similar increases in rilpivirine and efavirenz arms
● Resistance with virologic failure
- Rilpivirine: 6.4%; efavirenz: 2.3%
● Safety
- Lower incidence of adverse events of interest compared with efavirenz
- Most adverse events emerge during the first 4 weeks of therapy
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].Molina J-M, et al. Lancet. 2011;378:238-246.Cohen CJ, et al. Lancet. 2011;378:229-237.Rashbaum B, et al. 51st ICAAC. Chicago, 2011. Abstract H2-805.Rimsky L, et al. JAIDS. 2012;59:39-46.
52
STAR Study:Design (96 Weeks)
Randomization1:1
Efavirenz/Emtricitabine/Tenofovir DFOnce Daily
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
Emtricitabine/Rilpivirine/Tenofovir DFOnce Daily
Phase 3b study(96 weeks)
Treatment-naïve
Open-labelHIV RNA >2500 copies/mL
Any CD4 countGenotypic sensitivity(EFV, FTC, RPV, TDF)
Non-inferiority(12% margin)
Single-Tablet, Once-Daily Regimens
PrimaryEndpointWeek 48
HIV RNA<50 Copies/mL
53
STAR Study:Baseline Demographics
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
54
STAR Study (Week 48):Virologic and Immunologic Outcomes
Pat
ien
ts (
%)
HIV RNA <50 Copies/mL CD4 Cell Gain
85.8%
FTC/RPV/TDF(n=394)
EFV/FTC/TDF(n=392)
81.6%
CD
4 G
ain
(ce
lls/m
m3 )
200191
P=0.34
Difference (%):Difference (%):4.1 (-1.1, 9.2)4.1 (-1.1, 9.2)
Non-inferiority criteria met.
FTC/RPV/TDF(n=394)
EFV/FTC/TDF(n=392)
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
55
STAR Study (Week 48):Virologic Outcomes By Baseline HIV RNA
Pat
ien
ts (
%)
HIV RNA <50 Copies/mL) Virologic Failure
89%
80%
<100K(n=260/250)
FTC/RPV/TDF EFV/FTC/TDF
82% 82%
>100K(n=134/142)
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
Baseline HIV RNA
Difference (%):Difference (%):7.2 (1.1, 13.4)7.2 (1.1, 13.4) Difference (%):Difference (%):
-1.8 (-11.1, 7.5)-1.8 (-11.1, 7.5)
Pat
ien
ts (
%)
5%10%
<100K(n=260/250)
FTC/RPV/TDF EFV/FTC/TDF
3%9%
>100-500K(n=98/117)
Baseline HIV RNA
>500K*(n=36/25)
25%
16%
*Analysis of the >500K stratum was a post-hoc.
56
Emtricitabine/Rilpivirine/Tenofovir DF:Dosing and Safety Considerations
● Meal restrictions
- Take with meal
● Drugs that increase gastric pH (eg, proton-pump inhibitors) may decrease plasma concentrations of rilpivirine
● Adverse events (less common with rilpivirine compared with efavirenz)
- Rash
- Neuropsychiatric symptoms
● Resistance (rilpivirine)
- Most common RAM is E138K (leads to cross resistance to etravirine)
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.Johnson VA, et al. Top Antivir Med. 2011;19:156-164.
57
Evidence Supports Combination ART for Prevention of HIV Transmission
● Transmission only occurs from persons with HIV
● HIV RNA level is single greatest risk factor for HIV transmission
● Combination ART can lower HIV RNA level to undetectable levels
● Observational evidence in heterosexual couples
● Previous modeling work suggests considerable potential
● Knowing one’s HIV status is key to prevention with combination ART
● When to start combination ART is not known for certainty
58
New Electronic Evaluation ProcessNew Electronic Evaluation Process
● Please clearly print your information on the Sign-in Sheet
● You will receive an electronic evaluation to the email address provided within 1 business day
● Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed
● Completion Is Required for CME/CNE/CPE credit and future attendance
● Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
59
Outcomes Measurement ReminderOutcomes Measurement Reminder
● We are required to assess “changes in learners’ competence, performance or patient outcomes achieved as a result of their participation in a CME/CNE/CPE sponsored educational activity”
● As a result of this requirement you will receive a short survey via email 8 to 12 weeks after completing this course
- We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey
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