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
- 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 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 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
2
Educator
Lisa Hightow-Weidman, MD, MPH
Associate Professor
University of North Carolina at Chapel Hill
● Disclosures
-
3
Grants/Research Support: n/a
Consultant: n/a
Speakers’ Bureau: Gilead, Janssen
Stock Shareholder: n/a
Other Financial or Material Support: n/a
Accreditation 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.
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.
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.
4
Faculty
5
CME Course Director
Harold A. Kessler, MD
Content Development and Training
Eric S. Daar, MD
Professor of Medicine and
Immunology/Microbiology
Associate Director,
Section of Infectious Diseases
Rush University Medical Center
Chicago, Illinois
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Torrance, California
Professor of Medicine
David Geffen School of Medicine at UCLA
Los Angeles, California
CME Reviewer
David M. Simon, MD, PhD
CNE Reviewer
Allison R. Webel, RN, PhD
Associate Professor
Section of Infectious Diseases
Rush University Medical Center
Chicago, Illinois
Instructor and KL2 Clinical
Research Scholar
Frances Payne Bolton School of Nursing
Case Western Reserve University
Cleveland, Ohio
Faculty 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
Abbott Laboratories,
GlaxoSmithKline, Merck
None
None
None
Stock
shareholder
Other financial or
material support
6
Faculty Disclosures
7
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
Opinions 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 uses
of a commercial product or an investigational use of a
product not yet approved for this purpose
Please consult the full prescribing information before using
any medication mentioned in this program
8
New 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
9
Learning Objectives
(CME/CNE and CPE)
CPE
CME/CNE
●
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
10
●
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
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
11
Worldwide Treatment and
Prevention Gaps (2011)
● On ART: 8 million
● Number needing ART: 15 million
● New infections: 2 million
● People were waiting to become treatmenteligible, sicken, or die: ~24 million
● Estimated coverage of ART in low- and middleincome countries: 36%
Granich R, et al. Curr Opin HIV AIDS. 2013;8:41-49.
12
Chronic HIV in the US:
Underdiagnosed and Undertreated
Number (in ‘000s)
1,106,4001,200,000
~80%
Diagnosed
874,056960,000
~40%
Treated
437,028489,600
~20% of All
HIV-Infected
Are HIV RNA
<50 copies/mL
209,773376,992
Prevalence
Diagnosed
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.
13
Treated
Viral Suppression
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
-
14
Education about risks
Behavioral interventions to decrease risk
Harm reduction
Vaccines
The Shift Towards Earlier
Initiation 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
15
Simultaneous Use of Different Classes
of Prevention Strategies
Biomedical
Interventions
Structural
Interventions
Combination
HIV
Prevention
Community
Interventions
16
HIV Testing,
Linkage to Care,
Expanded ART
Coverage
Individual and
Small Group
Behavioral
Interventions
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.
17
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.
18
PrEP Trial Results
● 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)
19
CDC Interim Guidance for Healthcare
Providers: 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.
20
CDC Interim Guidance for Healthcare
Providers: 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.
21
CDC Interim Guidance for Healthcare
Providers: 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.
22
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
23
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.
24
When to Start Treatment
2/2013
DHHS
Guidelines
2012
IAS-USA
Guidelines
CD4 Count
HIV RNA
Clinical Category
(cells/mm3)
(copies/mL)
AIDS-defining illness or severe
symptoms
Any value
Any value
Treat
<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
Asymptomatic
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.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308:387-402.
25
DHHS Guidelines:
Preferred Regimens
NNRTI
PI
Efavirenz1/emtricitabine2/tenofovir DF3
Atazanavir4 + ritonavir + emtricitabine2/tenofovir DF3
Darunavir + ritonavir (qd) + emtricitabine2/tenofovir DF3
INSTI
Raltegravir + emtricitabine2/tenofovir DF3
Pregnant Lopinavir/r bid + zidovudine/lamivudine2
women
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.
26
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.
27
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
28
Higher pill count
Gastrointestinal toxicity
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.
29
Potential Therapeutic Targets
CCR5
Inhibitors
Fusion
Inhibitors
Cytoplasm
Reverse
Transcriptase
Inhibitors
Integrase
Inhibitors
30
Protease
Inhibitors
Nucleus
Program Overview
● Treatment challenges/clinical needs
● New antiviral drugs/formulations
31
Study 102: QUAD Versus
Efavirenz/Emtricitabine/Tenofovir DF
Single-Tablet, Once-Daily Regimens
Phase 3 study
(192 weeks)
Treatment-naïve
Double-blind
HIV RNA >5000 copies/mL
Any CD4 count
Non-inferiority
(12% margin)
Randomization
1:1
Elvitegravir 150 mg/Cobicistat 150 mg/
Emtricitabine/Tenofovir DF (n=348)
Efavirenz 600 mg/
Emtricitabine/Tenofovir DF (n=352)
Primary
Endpoint
Week 48
HIV RNA
<50 Copies/mL
Sax PE, et al. Lancet. 2012;379:2439-2448.
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
32
Study 102:
Baseline Demographics
EVG/COBI/FTC/TDF
(n=348)
EFV/FTC/TDF
(n=352)
Males (%)
88
90
Mean age (years)
38
38
Race (%)
White
Black
61
30
64
26
HIV RNA
Median (log10 copies/mL)
>100K copies/mL (%)
4.75
34
4.78
33
Median CD4 (cells/mm3)
<200 cells/mm3 (%)
200 to 350 cells/mm3 (%)
351 to 500 cells/mm3 (%)
>500 cells/mm3 (%)
376
12
32
32
23
383
15
27
39
20
Sax PE, et al. Lancet. 2012;379:2439-2448.
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
33
Study 102:
Virologic and Immunologic Outcomes
CD4 Cell Gain
HIV RNA <50 Copies/mL
EVG/COBI/FTC/TDF
Difference (%):
3.6 (-1.6, 8.8)
84%
273
84% 82%
239*
Patients (%)
206
48
96
48
96
(n=348/352)
(n=348/352)
(n=325/315)
(n=307/302)
Week
*P=0.009.
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
EFV/FTC/TDF
295
Difference (%):
2.7 (-2.9, 8.3)
CD4 Gain (cells/mm3)
88%
EVG/COBI/FTC/TDF
EFV/FTC/TDF
Week
Study 102: Virologic Outcomes
by Baseline HIV RNA
Baseline HIV RNA <100K Copies/mL
EVG/COBI/FTC/TDF
86%
85%
EVG/COBI/FTC/TDF
EFV/FTC/TDF
81%
84% 82%
81% 83%
Patients (%)
48
96
48
96
(n=348/352)
(n=230/236)
(n=348/352)
(n=230/236)
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.
35
EFV/FTC/TDF
Patients (%)
90%
Baseline HIV RNA >100K Copies/mL
Week
Study 102 (Week 96):
NNRTI, Integrase, and NRTI Resistance
EVG/COBI/FTC/TDF
(n=348)
EFV/FTC/TDF
(n=352)
Number of patients analyzed for resistance
With resistance to ART regimen
14
10
17
10
Any primary integrase resistance (number of patients)
E92Q
T66I
Q148R
N155H
9
7
1
1
3
Any primary NNRTI resistance (number of patients)
K103N
K101E/K
Y188Y/F/H/L
G190A/S
Any primary NRTI resistance (number of patients)
M184V/I
K65R
10
9
3
2
1
10
10
4
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
36
3
3
3
Study 102 (Week 96):
Safety and Tolerability
Week 96
EVG/COBI/FTC/TDF
EFV/FTC/TDF
(n=348)
(n=352)
Treatment-emergent adverse events (%)
Nausea
Abnormal dreams
Insomnia
Dizziness
Rash
22
15
11
8
7
15
28
16
25
14
Grade 3/4 creatine kinase abnormality (%)
7
14
-13.8
-0.8
+9
+9
+6
+4
+18
+16
+7
+9
Median change in eGFR (mL/min) (C-G)
Mean change in lipids (mg/dL)
Total cholesterol
LDL-C
HDL-C
Triglycerides
Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.
37
Study 103: QUAD Versus
Atazanavir/r + Emtricitabine/Tenofovir DF
Once-Daily Regimens
Phase 3 study
(192 weeks)
Treatment-naïve
Double-blind
HIV RNA >5000 copies/mL
Any CD4 count
Non-inferiority
(12% margin)
Randomization
1:1
Elvitegravir/Cobicistat/
Emtricitabine/Tenofovir DF (n=353)
Atazanavir/r +
Emtricitabine/Tenofovir DF (n=355)
Primary
Endpoint
Week 48
HIV RNA
<50 Copies/mL
DeJesus E, et al. Lancet. 2012;379:2429-2438.
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
38
Study 103:
Baseline Demographics
EVG/COBI/FTC/TDF
(n=353)
ATV/r + FTC/TDF
(n=355)
Males (%)
92
89
Mean age (years)
38
38
Race (%)
White
Black
71
20
78
13
HIV RNA
Median (log10 copies/mL)
>100K copies/mL (%)
4.8
42
4.8
40
Median CD4 (cells/mm3)
<200 cells/mm3 (%)
200 to 350 cells/mm3 (%)
351 to 500 cells/mm3 (%)
>500 cells/mm3 (%)
351
15
35
35
16
366
11
35
34
20
DeJesus E, et al. Lancet. 2012;379:2429-2438.
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
39
Study 103:
Virologic and Immunologic Outcomes
CD4 Cell Gain
HIV RNA <50 Copies/mL
EVG/COBI/FTC/TDF
Difference (%):
2.7 (-2.1, 7.5)
87%
256
83% 82%
Patients (%)
207
261
211
48
96
48
96
(n=353/355)
(n=353/355)
(n=334/321)
(n=316/315)
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.
40
ATV/r + FTC/TDF
Difference (%):
1.1 (-4.5, 6.7)
CD4 Gain (cells/mm3)
90%
EVG/COBI/FTC/TDF
ATV/r + FTC/TDF
Week
Study 103: Virologic Outcomes
by Baseline HIV RNA
Baseline HIV RNA <100K Copies/mL
EVG/COBI/FTC/TDF
93%
Baseline HIV RNA >100K Copies/mL
EVG/COBI/FTC/TDF
ATV/r + FTC/TDF
90%
85%
82% 80%
Patients (%)
48
96
48
96
(n=203/214)
(n=203/214)
(n=150/141)
(n=150/141)
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.
41
82%
Patients (%)
84% 84%
ATV/r + FTC/TDF
Week
Study 103 (Week 96):
Resistance
EVG/COBI/FTC/TDF
(n=353)
ATV/r + FTC/TDF
(n=355)
Number of patients
Analyzed for resistance
With resistance to ART regimen
12
6
8
0
Any primary integrase resistance
(number of patients)
E92Q
T66I
Q148R
N155H
5
2
1
2
2
Any primary NRTI resistance
(number of patients)
M184V/I
K65R
5
5
1
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
42
0
Study 103 (Week 96):
Safety and Tolerability
EVG/COBI/FTC/TDF
(n=353)
ATV/r + FTC/TDF
(n=355)
Treatment-emergent adverse events (%)
Diarrhea
Nausea
Upper respiratory infection
Headache
Fatigue
Ocular icterus
25
21
19
17
15
1
31
21
20
15
16
14
Grade 3/4 creatine kinase abnormality (%)
7
10
-12.3
-9.5
+14
+14
+7
+5
+8
+11
+5
+16
Median change in eGFR (mL/min) (C-G)
Mean change in lipids (mg/dL)
Total cholesterol
LDL-C
HDL-C
Triglycerides
Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.
43
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF:
Dosing and Safety Considerations
● Meal restrictions
-
Take with meal
● Adverse events
-
Diarrhea, nausea
•
-
Early decrease in estimated GFR from cobicistat
•
-
Comparable with ATV/r, usually mild and rarely leads to drug
discontinuation
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.
44
ECHO and THRIVE Studies:
Study Design (96 Weeks)
Phase 3 Studies
Treatment-naïve, HIV RNA >5000 copies/mL, no NNRTI resistance-associated mutations
Randomization
1:1
ECHO
(n=690)
Rilpivirine 25 mg qd +
Emtricitabine/Tenofovir DF qd
Efavirenz 600 mg qd +
Emtricitabine/Tenofovir DF qd
Randomization
1:1
THRIVE
Rilpivirine 25 mg qd +
2 NRTIs*
(n=678)
Efavirenz 600 mg qd +
2 NRTIs
Primary endpoint: non-inferiority at week 48 (lower confidence interval <12%).
*Investigator’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.
45
ECHO and THRIVE Studies:
Baseline Demographics
ECHO
Rilpivirine
(n=346)
Placebo
(n=344)
Rilpivirine
(n=340)
Placebo
(n=338)
Males (%)
77
80
74
72
Ethnicity (%)
White
Black
62
26
60
23
61
22
60
22
HIV RNA
Median (log10 copies/mL)
<100K copies/mL (%)
>100K copies/mL (%)
5
52
48
5
47
53
5
55
45
5
49
51
Median CD4 (cells/mm3)
240
242
263
263
Emtricitabine/tenofovir DF (%)
Zidovudine/lamivudine (%)
Abacavir/lamivudine (%)
100
0
0
100
0
0
60
30
10
60
30
10
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.
46
THRIVE
ECHO and THRIVE Studies:
HIV RNA <50 Copies/mL(ITT-TLOVR)
Rilpivirine
Efavirenz
100
Patients (%)
80
83%
83%
CD4
+196
cells/µL
CD4
+182
cells/µL
86%
78%
78%
CD4
+228
cells/µL
CD4
+219
cells/µL
60
40
20
0
CD4
+189
cells/µL
CD4
+171
cells/µL
ECHO
THRIVE
Pooled Data
(n=346/344)
(n=340/338)
(n=686/682)
Week 48
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
82%
Week 96
Pooled ECHO/THRIVE Post-Hoc Analysis:
HIV RNA <50 Copies/mL (Week 96)
By Baseline CD4
(copies/mL)
(cells/mm3)
Rilpivirine
Efavirenz
84%
80
100
80%
70%
75%
60
40
20
0
<100K
(n=368/329)
>100K
(n=318/353)
All patients received emtricitabine/tenofovir DF.
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].
48
HIV RNA <50 Copies/mL (%)
HIV RNA <50 Copies/mL (%)
100
By Baseline HIV RNA
Rilpivirine
Efavirenz
80
69%
60
75
71% %
81% 79
%
85%
79%
56%
40
20
0
<50
(n=34/36)
50-<200 200-<350 >350
(n=194/175) (n=313/307) (n=144/164)
Pooled ECHO/THRIVE (Week 96):
Discontinuations and Virologic Failure
Rilpivirine
(n=686)
Efavirenz
(n=682)
HIV RNA <50 copies/mL (%)
78
78
Virologic failure (%)
Overall
Rebounder
Never suppressed
12
6
5
6
4
2
Discontinued due to (%)
Adverse events
Other reasons
4
7
8
8
0.1
1.0
Death (%)
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].
49
Pooled ECHO/THRIVE (Week 96):
Safety
Rilpivirine
(n=686)
Efavirenz
(n=682)
Most common adverse events of interest (%)
Any neurologic
Dizziness
Any psychiatric
Abnormal dreams/nightmares
Rash (any type)
17
8
16
8
4
38*
27*
22*
13†
15*
Grade 2-4 laboratory abnormality (%)
Total cholesterol
LDL-C
AST
ALT
7
7
6
6
22*
18*
10
11
*P<0.0001 and †P=0.0039 versus rilpivirine.
Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].
50
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
-
51
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.
STAR Study:
Design (96 Weeks)
Single-Tablet, Once-Daily Regimens
Phase 3b study
(96 weeks)
Treatment-naïve
Open-label
HIV RNA >2500 copies/mL
Any CD4 count
Genotypic sensitivity
(EFV, FTC, RPV, TDF)
Non-inferiority
(12% margin)
Randomization
1:1
Emtricitabine/Rilpivirine/Tenofovir DF
Once Daily
Efavirenz/Emtricitabine/Tenofovir DF
Once Daily
Primary
Endpoint
Week 48
HIV RNA
<50 Copies/mL
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
52
STAR Study:
Baseline Demographics
FTC/RPV/TDF
(n=394)
EFV/FTC/TDF
(n=392)
Males (%)
93
93
Mean age (years)
37
35
Race (%)
White
Black
Latino
68
25
15
67
24
19
HIV RNA
Median (log10 copies/mL)
>100K copies/mL (%)
4.8
34
4.8
36
Median CD4 (cells/mm3)
396
385
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
53
STAR Study (Week 48):
Virologic and Immunologic Outcomes
HIV RNA <50 Copies/mL
CD4 Cell Gain
Difference (%):
4.1 (-1.1, 9.2)
81.6%
191
FTC/RPV/TDF
EFV/FTC/TDF
FTC/RPV/TDF
EFV/FTC/TDF
(n=394)
(n=392)
(n=394)
(n=392)
Non-inferiority criteria met.
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
54
P=0.34
CD4 Gain (cells/mm3)
200
Patients (%)
85.8%
STAR Study (Week 48):
Virologic Outcomes By Baseline HIV RNA
HIV RNA <50 Copies/mL)
FTC/RPV/TDF
Difference (%):
7.2 (1.1, 13.4)
89%
EFV/FTC/TDF
FTC/RPV/TDF
EFV/FTC/TDF
Difference (%):
-1.8 (-11.1, 7.5)
80% 82%
Patients (%)
Patients (%)
82%
Virologic Failure
25%
16%
5% 3%
<100K
>100K
<100K
>100-500K
>500K*
(n=260/250)
(n=134/142)
(n=260/250)
(n=98/117)
(n=36/25)
Baseline HIV RNA
*Analysis of the >500K stratum was a post-hoc.
Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4):18221. Abstract O425.
55
10% 9%
Baseline HIV RNA
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.
56
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
57
New 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
58
Outcomes 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
59