Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for
Achieving Long-term Viral Suppression
Presented as a Midday Symposium and Live Webinar at the
50th ASHP Midyear Clinical Meeting and Exhibition
Monday, December 7, 2015
New Orleans, Louisiana
www.cemidday.com
Sponsored by the American Society of Health-System Pharmacists (ASHP) and planned by ASHP Advantage, a division of ASHP.
Supported by an educational grant from Merck
© 2015 American Society of Health‐System Pharmacists
Please be advised that this activity is being audio and/or video recorded for archival purposes and, in some cases, for repurposing of the content for enduring materials.
2 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Agenda
11:30 a.m. – 11:40 a.m. Welcome and Introductions Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP 11:40 a.m. – 11:50 a.m. HIV Epidemiology and Engagement in Care
Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP 11:50 a.m. – 12:10 p.m. Acute HIV Infection
Joseph A. DeSimone, Jr. M.D., FIDSA, AAHIVS 12:10 p.m. – 12:30 p.m. Switching ART
Joseph A. DeSimone, Jr. M.D., FIDSA, AAHIVS 12:30 p.m. – 12:50 p.m. Hepatitis C Co-infection Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP 12:50 p.m. – 1:00 p.m. Faculty Discussion and Audience Questions All Faculty
Faculty
Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP, Activity Chair Associate Professor, Department of Pharmacy Practice Jefferson College of Pharmacy Clinical Pharmacy Specialist, HIV Ambulatory Care Jefferson Infectious Diseases Associates Thomas Jefferson University Philadelphia, Pennsylvania Joseph A. DeSimone, Jr. M.D., FIDSA, AAHIVS Professor of Medicine Director, Infectious Diseases Fellowship Program Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania
3 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Disclosure Statement
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for
Commercial Support and the Accreditation Council for Pharmacy Education’s Standards for Commercial
Support, ASHP Advantage requires that all individuals involved in the development of activity content
disclose their relevant financial relationships. A person has a relevant financial relationship if the
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All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP
Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP
Advantage identifies and resolves conflicts of interest prior to an individual’s participation in
development of content for an educational activity.
Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP, declares he received a research grant from
Merck.
All other faculty and planners report no financial relationships relevant to this activity.
4 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Activity Overview
The epidemic of human immunodeficiency virus (HIV) infection in the United States has changed
dramatically in the last 30 years. The widespread use of antiretroviral therapy, in particular, can
significantly suppress HIV replication, restore a patient’s immune function, and has resulted in a
significant decline in HIV-related morbidity and mortality. As a result, patients on long-term therapy that
maintain viral suppression can now manage their infection as a chronic illness and are likely to
experience a near-normal life expectancy. Despite the remarkable advances in the management of
patients living with HIV infection in the United States, challenges to successful HIV care remain.
This educational activity will apply emerging evidence and current practice guidelines to address
contemporary challenges in achieving long-term viral suppression among HIV positive patients
commonly encountered in the ambulatory care setting.
Learning Objectives
At the conclusion of this application-based educational activity, participants should be able to
Outline the diagnosis and management of acute HIV infection.
Select patients who are appropriate candidates for switching antiretroviral regimens to improve
convenience, safety or tolerability.
Demonstrate the current approach to managing patients with HIV and hepatitis C co-infection.
Additional Educational Opportunities about HIV Coming in 2016
Web-based activity - Based on today’s live symposium (1.5 hours of CE, please note that individuals
who claim CE credit for the live symposium or webinar are ineligible to claim credit for the web-
based activity)
For more information and to sign up to receive e-mail updates
about this educational series, visit
www.cemidday.com
5 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Continuing Education Accreditation
The American Society of Health-System Pharmacists is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy education. This
activity provides 1.5 hours (0.15 CEUs – no partial credit) of continuing pharmacy
education credit.
Live Activity ACPE #: 0204-0000-15-473-L02-P
On-Demand Activity ACPE #: 0204-0000-15-473-H02-P
The American Society of Health-System Pharmacists is accredited by the Accreditation
Council for Continuing Medical Education to provide continuing medical education for
physicians.
The American Society of Health-System Pharmacists designates this live activity for a maximum of 1.5
AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
Complete instructions for processing continuing education credit online are listed on the last page.
Webinar Information
Visit www.cemidday.com to find:
Webinar registration link
Group viewing information and technical requirements
6 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP Associate Professor, Department of Pharmacy Practice Jefferson College of Pharmacy Clinical Pharmacy Specialist, HIV Ambulatory Care Jefferson Infectious Diseases Associates Thomas Jefferson University Philadelphia, Pennsylvania Jason J. Schafer, Pharm.D., M.P.H., BCPS, AAHIVP, is Associate Professor of Pharmacy Practice at the Jefferson College of Pharmacy and Clinical Pharmacy Specialist, HIV Ambulatory Care, at Thomas Jefferson University in Philadelphia, Pennsylvania. Dr. Schafer received his Doctor of Pharmacy degree from Duquesne University and completed a pharmacy practice residency at the Mercy Hospital of Pittsburgh and a second residency specializing in infectious diseases at the Ohio State University Medical Center. He received his Master of Public Health degree from the Jefferson School of Population Health. He is a board-certified pharmacotherapy specialist (BCPS) and is certified by the American Academy of HIV Medicine (AAHIVM) as a practicing HIV Pharmacist (AAHIVP). Dr. Schafer’s clinical practice site is an HIV specialty ambulatory care clinic in Philadelphia where he provides medication therapy management services. He also provides service to the AAHIVM on its Pharmacist and Credentialing Committees. Dr. Schafer has published numerous articles on HIV medicine and pharmacotherapy in the medical literature including the ASHP Guidelines on Pharmacist Involvement in HIV Care. He has also been active in ASHP most recently serving as the Infectious Diseases Network Facilitator and as Director at Large for the Section of Clinical Specialists and Scientist’s Executive Committee.
7 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Joseph A. DeSimone, Jr. M.D., FIDSA, AAHIVS Professor of Medicine Director, Infectious Diseases Fellowship Program Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania Joseph A. DeSimone, Jr., M.D., FACP, FIDSA, is Professor of Medicine and Program Director for the Infectious Diseases Fellowship Program at the Sidney Kimmel Medical College, at Thomas Jefferson University in Philadelphia, Pennsylvania. Dr. DeSimone graduated from Hahnemann University School of Medicine where he also completed both his Internal Medicine residency and Infectious Diseases fellowship. He is a fellow of the Infectious Diseases Society of America (FIDSA) and a Practicing HIV Specialist (AAHIVS). He is responsible for teaching infectious diseases and HIV to medical students, internal medicine residents, and infectious diseases fellows at Thomas Jefferson University. Dr. DeSimone has provided clinical care for HIV-infected patients at Thomas Jefferson University for over 15 years and currently cares for over 300 HIV-infected patients in his practice. He has acted as the principal or co-principal investigator for dozens of clinical trials investigating antiretroviral therapy for persons with HIV infection. Dr. DeSimone has authored numerous publications in peer-reviewed journals and abstract presentations at national meetings. He has received numerous teaching awards while at Thomas Jefferson University including the Dean’s Award for Excellence in Education from the Sidney Kimmel Medical College and Induction into the Gold Humanism Honor Society.
8 © 2015 American Society of Health‐System Pharmacists
CE IN THE MIDDAY
This activity is sponsored by the American Society of Health-System Pharmacists (ASHP) and planned by ASHP Advantage, a division of ASHP.
Supported by an educational grant from Merck
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving
Long‐term Viral Suppression
Jason J. Schafer Pharm.D., M.P.H, BCPS, AAHIVP
Activity ChairAssociate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
Joseph A. DeSimone, Jr. MD, FIDSA, AAHIVSProfessor of Medicine
Director, Infectious Diseases Fellowship Program
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Disclosures
• Jason J. Schafer, Pharm.D., M.P.H., BCPS,AAHIVP, declares he received a research grantfrom Merck.
• All other faculty and planners report nofinancial relationships relevant to this activity.
Learning Objectives
• Outline the diagnosis and management ofacute HIV infection.
• Select patients who are appropriatecandidates for switching antiretroviralregimens to improve convenience, safety ortolerability.
• Demonstrate the current approach tomanaging patients with HIV and hepatitis Cco‐infection.
9 © 2015 American Society of Health‐System Pharmacists
CE IN THE MIDDAY
HIV Epidemiology and Engagement in Care
Jason J. Schafer Pharm.D., M.P.H, BCPS, AAHIVP
Activity ChairAssociate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
HIV Infection in the U.S.
Centers for Disease Control and Prevention, HIV/AIDS Surveillance.http://www.cdc.gov/hiv/library/reports/surveillance/ (accessed 2015 Oct).
Year of Diagnosis or Death
Diagnoses or Death (x 1000)
AIDS Diagnoses and Deaths in the United States, 1985‐2012
CDC National HIV Surveillance System and Medical Monitoring ProjectHIV Care Continuum. https://www.aids.gov/federal‐resources/policies/care‐continuum/
HIV Infection in the USPatient engagement in the continuum of HIV Care
Diagnosed
Antiretroviral Therapy
Virally Suppressed
0% 20% 40% 60% 80% 100%
86%
36%
30%
• Of the 1.2 million people living with HIV in the U.S. in 2011, an estimated 86% were diagnosed.
• 14% (or 1 in 7 people living with HIV) were unaware of their infection
• Patient engagement decreases at each stage in the continuum
Engaged in Care 40%
10 © 2015 American Society of Health‐System Pharmacists
CDC National HIV Surveillance System and Medical Monitoring Project.Skarbinski, et al. JAMA Intern Med. 2015;175(4):588‐596.
Diagnosed
0% 20% 40% 60% 80% 100%
86%
Engaged in Care 40%
HIV Infection in the USPatient engagement and Transmission of HIV
92% of new HIV infections are attributable to people with HIV who are not in medical care, including those who are not diagnosed
CDC National HIV Surveillance System and Medical Monitoring ProjectHIV Care Continuum. https://www.aids.gov/federal‐resources/policies/care‐continuum/
HIV Infection in the USPatient engagement in the continuum of HIV Care
Virally Suppressed
0% 20% 40% 60% 80% 100%
30%
66% diagnosed but not in care
A
B
C
D30%
• Of the 70% of people living with HIV who are not virally suppressed:
A. 66% are diagnosed, but not engaged in regular HIV careB. 20% do not know they are infectedC. 10% are prescribed ART, but have not yet achieved viral suppressionD. 4% are in HIV care, but are not prescribed ART
• Closing the gaps
– Improvements in HIV testing and diagnosis
– Emerging strategies for linking and retainingpatients in care
– Evolving recommendations for when to initiateantiretroviral therapy
– Achieving and maintaining viral suppression
CDC National HIV Surveillance System and Medical Monitoring ProjectHIV Care Continuum. https://www.aids.gov/federal‐resources/policies/care‐continuum/
HIV Infection in the USPatient engagement in the continuum of HIV Care
11 © 2015 American Society of Health‐System Pharmacists
CE IN THE MIDDAY
Acute HIV Infection
Joseph A. DeSimone, Jr. MD, FACP, AAHIVS
Professor of Medicine
Director, Infectious Diseases Fellowship Program
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania
Patient Case‐August 2015
• PT is a 37 YO AA female; ER 8/17/15.
• 5 days abdominal pain, dysuria, foul‐smelling urine, vomiting.
• Observed overnight, dx pyelonephritis, sent home with oral cephalosporin.
• While in observation unit, offered HIV screening per EDprotocol.
• HIV Antigen(Ag)/Antibody (Ab) 4th‐generation enzyme immunoassay (EIA) reactive.
• Reports prior negative HIV testing.
• New monogamous male sexual partner 6 months ago after 7 years of abstinence. Partner serostatus unknown.
In patients with a reactive 4th‐generation HIV Ag/Ab result, what test should be performed next?
a. HIV‐1 Western blot
b. HIV‐2 Western blot
c. HIV viral RNA quantitative assay (viral load)
d. HIV‐1/HIV‐2 discriminatory immunoassay
e. CD4 cell count
12 © 2015 American Society of Health‐System Pharmacists
Graphic Bar on left
CDC. http://www.cdc.gov/hiv/pdf/hivtestingalgorithmrecommendation‐final.pdf (accessed 2015 Oct).
If reactive HIV‐1/2 Antigen/Antibody Combination Immunoassay…
.CDC and APHL. http://stacks.cdc.gov/view/cdc/23447. Version June 27, 2014.
HIV‐1/HIV‐2 differentiation assay (Multispot)
http://www.fda.gov/downloads/Biolog...remarketApprovalsPMAs/ucm091384.pdf (accessed 2015 Oct).
13 © 2015 American Society of Health‐System Pharmacists
The HIV‐1/HIV‐2 differentiation assay (Multispot) results are both non‐reactive. What should be done next for PT?a. HIV‐1 Western blot
b. CD4 cell count
c. HIV viral RNA quantitative assay (viral load)
d. Inform the patient that she is definitelyinfected with HIV
e. Inform the patient she is definitely notinfected with HIV
CDC. http://www.cdc.gov/hiv/pdf/hivtestingalgorithmrecommendation‐final.pdf (accessed 2015 Oct).
CDC and APHL: Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens
CDC and APHL. http://stacks.cdc.gov/view/cdc/23447. Version June 27, 2014.
Perform HIV‐1/2 Antigen/Antibody Combination Immunoassay
Perform HIV‐1/2 AntibodyDifferentiation Immunoassay
HIV-1 (+)HIV-2 (-)
HIV-1 AntibodiesDetected
HIV-1 (-)HIV-2 (+)
HIV-2 AntibodiesDetected
HIV-1 (+)HIV-2 (+)HIV Antibodies
Detected
HIV-1 (-) or IndeterminateHIV-2 (-)
Perform HIV-1Nucleic Acid Test
AcuteHIV-1 Infection
Negative forHIV-1 Infection
Reactive Nonreactive
Negative for HIV‐1 and HIV‐2
Antibodies and p24Ag
Reactive Nonreactive
HIV-1Infection
HIV-2Infection
DualHIV-1 and HIV-2
Infection
Note: new algorithm may not be uniformly adopted in all settings. If a rapid 3rd generation test is used with a positivie test result, confirmation is needed with a more specific test (eg, Western Blot).
14© 2015 American Society of Health‐System Pharmacists
See page 35 for enlarged view
See page 35 for enlarged view
Adapted from: Fauci AS et al. Ann Intern Med. 1996; 124:654.
Acute (Primary, Early) HIV Infection
Anubha Dubey, 2014, Association Rules for Diagnosis of Hiv‐Aids, Computational Molecular Biology, Vol.4, No.3 26‐33 (doi: 10.5376/cmb.2014.04.0003)/
Unexpected Clinical Manifestations of Primary HIV‐1 Infection
Braun D et al. Clin Infect Dis. 2015; 61:1013‐1021.
15© 2015 American Society of Health‐System Pharmacists
See page 36 for enlarged view
Awareness of Serostatus Among People with HIV, and Estimates of Transmission
~20% Unaware
of Infection
~80% Aware of Infection
People Living with HIV/AIDS:1,200,000
New Sexual Infections Each Year: ~50,000
account for…
~49% of New
Infections
~51% of New
Infections
Hall HI et al. AIDS. 2012; 26;893‐6.
PT comes to office 5 days later to learn of confirmed diagnosis. HIV viral load is >10 million copies; CD4 count is 600 cells/mm3.Should this patient be treated with ART and when?
a. Yes, immediately (today)
b. Yes, in 4 weeks (after genotype available)
c. No, since CD4 count is >500 cells/mm3.
d. Not yet, since she needs time to process hernew diagnosis.
e. Not sure
New York State Department of Health AIDS Institute: www.hivguidelines.org.
16© 2015 American Society of Health‐System Pharmacists
U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/guidelines (accessed 2015 April).
Providing same day, observed ART to newly diagnosed HIV+
outpatients is associated with improved virologic suppression
Christopher D. Pilcher, Hiroyu H. Hatano, Aditi Dasgupta, Diane Jones, Sandra Torres, Fabiola Calderon, Erin Demicco, Wendy
Hartogensis, Clarissa Ospina‐Norvell, Elvin Geng, Monica Gandhi, Diane Havlir
University of California, San Francisco
San Francisco General Hospital
0 30 60 90 120 150 180 210 240 270 300 330 360
Referral 1st Clinic Visit
1st PCPVisit
ART Prescribed
Viral load suppressed
2006‐2009CD4‐guided ART
2010‐2013Universal ART
Days since Referral
Milestones of care:SFGH, 2006‐2013
13237
218128
17© 2015 American Society of Health‐System Pharmacists
RAPID Demonstration ProjectJuly 2013‐December 2014
• Overall feasibility of a health systemsintervention for same‐day outpatient ART fornewly diagnosed HIV infection
• Deployed in context of extensive existing servicesfor navigation, linkage and retention
• Initially targeted to new patients with acute HIVinfection (HIV Ab – within 6 months)
• Extended in 2014 to include active opportunisticinfection (OI), CD4<200 cells/mm3
RAPIDIntervention Components
• Facilitation of same day appointments
• Flexible scheduling for providers (on‐call back‐up)
• ART regimens pre‐approved for use prior togenotyping or lab testing
• Available as 5‐day starter packs
• Accelerated process for health insuranceinitiation
• Recommendation for 1st dose to be takenobserved in the clinic
New SFGH patients, RAPID era: 2013‐4Indicator RAPID Cohort
(n=39)Universal ART
(n=47)P‐
value
Sociodemographics
Age: mean(range) 32 (21‐47) 35 (19‐68) NS
Male: n (%) 39 100% 43 92% NS
Non‐white ethnicity
23 59% 34 71% NS
Homeless 11 28% 13 25% NS
Uninsured 39 100% 47 100% NS
Staging
Acute (Ab‐ <6m) 21/30 70% 8/31 26% 0.001
Log10VL 4.9 (2.8‐6.6) 4.5 (1.6‐6.1) NS
CD4 mean (range) 474 (3‐1391) 417 (11‐1194) NS
VL=viral load
18© 2015 American Society of Health‐System Pharmacists
Uptake of same‐day ART
Days after ART offer/clinician visit
% on ART
90% 95%
0
10
20
30
40
50
60
70
80
90
100
0 1 7 30
RAPID
Universal
Indicator RAPID (n=39)
Universal(n=47)
Pvalue
Acceptability
Overall ART uptake 39 (100%) 40 (85%) NS
Engaged in care (appt <6 mos) 35 (90%) 40 (85%) NS
Transferred care 8 (21%) 11 (23%) NS
Provider switched 0 (0%) 0 (0%) NS
Safety
ART simplification 10 (26%) 0 (0%) 0.001
ART Toxicity 2 (5%) 0 (0%) NS
Genotype‐driven modification 0 (0%) 0 (0%) NS
*all outcomes determined as of last followup (up to 18 months post referral)
RAPID program era 2013‐4: acceptability and safety
561
Referral 1st Clinic Visit
1st PCPVisit
ART Prescribed
Viral load suppressed
Engagement Timeline, SFGH
CD4‐guided(2006‐9)
Universal(2010‐3)
RAPID
13237
Days since referral
19© 2015 American Society of Health‐System Pharmacists
Conclusions
• It was feasible to implement same‐day ART initiationfor outpatients with newly diagnosed HIV in a well resourced, public health clinic setting.
• Same day ART was highly acceptable to both patients and providers
• Same day ART was associated with improved rates ofvirologic suppression
• No excess toxicity or other adverse effects of starting ART immediately at the first visit were seen
• Expansion of the RAPID model citywide in 2015
8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19‐22, 2015. Abstract WEAD0105 LB.
Patient Case
• PT defers treatment at time of diagnosis.
• Returns to office one year later.
• Asymptomatic
• Viral load 200,000 copies/mL; CD4 600cells/mm3
• Estimated GFR 110 mL/min/1.73m2
• Takes no other meds
Is treatment with ART recommended for PT?
a. Yes
b. No
c. Not sure
20© 2015 American Society of Health‐System Pharmacists
START Study:Initiation of ART in Early Asymptomatic HIV Infection
Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print].
Permission from Practice Point Communications.
Multicontinental Study (n=4685)
HIV‐positive adults
Treatment‐naive
CD4 >500 cells/mm3
Randomization1:1 Immediate ART (n=2326)
Deferred ART (n=2359)(CD4 Declined to <350 cells/mm3 or AIDS‐related event)
Primary outcome a composite outcome of 2 major components:
• Any serious AIDS‐related event
‐ Death from AIDS or any AIDS‐defining event, Hodgkin’s lymphoma
• Any serious non–AIDS‐related event
‐ CVD (myocardial infarction, stroke, or coronary revascularization) or death from CVD, end‐stage renal disease (initiation ofdialysis or renal transplantation) or death from renal disease, liver disease (decompensated liver disease) or death from liver disease, non–AIDS‐defining cancer (except for basal‐cell or squamous cell skin cancer) or death from cancer, and any death not attributable to AIDS
5//2015: DSMB recommends stopping trial:Deferred arm offered ART
START Study Outcomes:Composite Primary Endpoint and its Components
• Immediate ART was superior to deferral of ART
– Both for serious and non‐seriousAIDS events
• Majority (68%) of the primary endpoints occurred in patientswith a CD4 >500 cells/mm3
• Similar significant reductionswere noted across all patient subgroups
• No increase in adverse events associated with immediate versus deferred ART
Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print].Permission from Practice Point Communications.
0
20
40
60
80
100
Number of Even
ts
AIDS‐Related
Non‐AIDS Related
Components(Serious Events)
CompositeEndpoint
96Deferred ART (n=2359)
Immediate ART (n=2326)
42
50
14
47
29
Number of Serious Events
57%Reduction(P<0.001)
72%Reduction(P<0.001)
39%Reduction(P=0.04)
When to Start Therapy:Balance Now Favors Early ART
• Drug toxicity• Preservation of limited Rx options• Risk of resistance (and transmission
of resistant virus)
• ↑ potency, durability, simplicity, safety of current regimens
• ↓ emergence of resistance• ↓ toxicity with earlier therapy• ↑ subsequent treatment op ons• Risk of uncontrolled viremia at all CD4
levels• ↓ transmission
Delayed ART Early ART
21© 2015 American Society of Health‐System Pharmacists
Recommendations for Initiating ART: Considerations
• “Patients starting ART should be willing andable to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.”
• Patients may choose to postpone ART
• Providers may elect to defer ART, based on anindividual patient’s clinical or psychosocialfactors, but ART should be started as soon asit is feasible to do so
July 201540 www.aidsetc.org
Per the DHHS 2015 guidelines, which of the following is currently recommended as a first‐line regimen for this patient?
a. Efavirenz/tenofovir disoproxil/emtricitabine(EFV/TDF/FTC)
b. Rilpivirine/tenofovir disoproxil/emtricitabine(RPV/TDF/FTC)
c. Atazanavir/ritonavir (ATV/r) plus TDF/FTC
d. Elvitegravir/cobicistat/TDF/FTC (EVG/cobi/TDF/FTC)
e. Darunavir/ritonavir (DRV/r) plus abacavir/lamivudine (ABC/3TC)
U.S. DHHS Guidelines, April 2015: What to Start
• Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) andAtazavavir/ritonavir (ATV/r), previously classified as “recommended,” are now “alternative regimens”
U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. April 2015.
*Only for pts who are HLA‐B*5701 negative. †Only for pts with pre‐ART CrCl ≥ 70 mL/min.
Recommended Regimens
Integrase strand transfer inhibitor (INSTI)‐based
Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC)*DTG plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)
Elvitegravir/cobicistat/TDF/FTC (EVG/COBI/TDF/FTC)†
Raltegravir (RAL) plus TDF/FTC
Ritonavir‐boosted protease inhibitor (PI/r)‐based
Darunavir/ritonavir (DRV/r)plus TDF/FTC
22© 2015 American Society of Health‐System Pharmacists
U.S. DHHS Guidelines, April 2015: What to Start
*Only for pts with pre‐ART HIV‐1 RNA < 100,000 copies/mL and CD4+ > 200 cells/mm3.†Only for pts with pre‐ART CrCl ≥ 70 mL/min.‡Only for pts who are HLA‐B*5701 negative.
• An alternative regimen may be the preferred regimen for some patients
U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. April 2015.
Alternative Regimens
NNRTI based EFV/TDF/FTCRPV/TDF/FTC*
PI based ATV/COBI + TDF/FTC†
ATV/r + TDF/FTC DRV/COBI + ABC/3TC‡
DRV/r + ABC/3TC‡
DRV/COBI + TDF/FTC†
Difference in 96‐wk cumulative incidence (97.5% CI)
-20 0-10 10 20
15% (10% to 20%)
7.5% (3.2% to 12%)
7.5% (2.3% to 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors DRV/r
Lennox JL, et al. Ann Intern Med. 2014;161:461‐471.
*Plus TDF/FTC.
ATV/r*RAL*DRV/r*
ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure
1.00
0.75
0.50
0.25
0.00
Cumulative Inciden
ce
Weeks Since Study Entry
0 24 48 64 80 96 112 128 144
Favors RALFavors RAL
SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in ART‐Naive Pts to Wk 144
• Open‐label extension, excluding pts with hepatitis B virus (HBV)• Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)
Virologic Success* Virologic Nonresponse No Virologic Data
Pts
(%
)
FavorsEFV/TDF/FTC
95% CI for Difference
0
Wk 48
Wk 96
Wk 144
7.4%
8.0%
8.3%
2.5%
2.3%
2.0% 14.6%
13.8%
12.3%
FavorsDTG + ABC/3TC
15%
8881 80
72 7163
5 6 7 8 107 7
13 1220
30
18
100
80
60
40
20
0
DTG + ABC/3TC QD (n = 414)EFV/TDF/FTC QD (n = 419)
Wk 48 96 144 Wk 48 96 144 Wk 48 96 144
*HIV‐1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.‐10% noninferiority margin.
-15%
Pappa K et al. ICAAC 2014. Abstract H‐647a.
23© 2015 American Society of Health‐System Pharmacists
See page 36 for enlarged view
See page 37 for enlarged view
FLAMINGO: DTG Superior to DRV/r in ART‐Naive Pts to Wk 96
Virologic Success Virologic Nonresponse No Virologic Data
FavorsDRV/r
95% CI for Difference
0%-12%
Wk 48
Wk 96
7.1%
12.4%
0.9%
4.7% 20.2%
13.2%
Subjects (%
)
FavorsDTG
25%
DTG 50 mg QD + 2 NRTIs (n = 242)
DRV/r 800 mg/100 mg QD + 2 NRTIs (n = 242)
Molina et al. HIV Drug Therapy Glasgow 2014; Glasgow, UK. Slides O153.
0
20
40
60
80
100
W48 W48 W48W96 W96 W96
90
8380
68
6 7 812
410 12
21
Comparing the Integrase Inhibitors
Together, the results of STARTMRK, GS 102 and 103, SINGLE, FLAMINGO, and ACTG 5257 suggest that integrase inhibitor–based regimens are the preferred starting regimens in
the majority of patients
CE IN THE MIDDAY
Switching ART
24© 2015 American Society of Health‐System Pharmacists
PT starts EVG/c/TDF/FTC. One year later: Viral load undetectable; CD4 count 900 cells/mm3; GFR now 70 mL/min/1.73 m2; HLA B‐5701 is positive. Next step?
a. Observe on EVG/c/TDF/FTC until GFR drops below
30 mL/min/1.73 m2
b. Switch EVG/c/TDF/FTC to Raltegravir (RAL) plusTDF/FTC
c. Switch EVG/c/TDF/FTC to DTG/ABC/3TC
d. Switch EVG/c/TDF/FTC to EVG/c/TAF/FTC
TAF (tenofovir alafenamide)
• Tenofovir disoproxil (TDF) associated withsevere renal adverse events in 1‐2%
• Conflicting data on reversibility of renalimpairment after discontinuation of TDF
• TAF is tenofovir (TFV) prodrug with 91% lesscirculating plasma tenofovir exposure andincreased intracellular concentration
Courtesy of Gilead Sciences
25© 2015 American Society of Health‐System Pharmacists
See page 37 for enlarged view
Study 109: Switch to Tenofovir Alafenamide‐Containing Single‐Tablet Regimen
Mills T, et al. J Int AIDS Soc. 2015;18(suppl 4):35. Abstract TUAB0102.Permission from Practice Point Communications.
Phase 2 study(96 weeks)
Treatment‐experienced
Open‐label
Non‐inferiority (12% margin)
HIV RNA <50 copies/mL
eGFR >50 mL/min
Randomization2:1
Continue Tenofovir DF‐Based Regimen (n=477)
Switch to E/C/F/TAF(n=959)
Primary EndpointWeek 48
HIV RNA <50 Copies/mL (FDA Snapshot)
E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.TAF 10 mg.Tenofovir DF‐based regimens:
• Elvitegravir/COBI/FTC/TDF (n=459).• Efavirenz/FTC/TDF (n=376).• Boosted atazanavir + FTC/TDF (n=601).
Median CD4: 662‐675 cells/mm3.Median eGFR: 106‐108 mL/min.
Study 109: Virologic Outcomes at Week 48 Following Switch to Tenofovir Alafenamide‐Containing Single‐Tablet Regimen
Mills T, et al. J Int AIDS Soc. 2015;18(suppl 4):35. Abstract TUAB0102.Permission from Practice Point Communications.
*Met non‐inferiority criteria (treatment difference: 4.1 [1.6‐6.7]).
0
20
40
60
80
100 97%*
All Patients(n=959/477)
EFV/FTC/TDF(n=251/125)
P<0.001
Remaining HIV RNA <50 Copies/mL
HIV RNA <50 Copies/mL (%
)
Prior ART Regimen
E/C/F/TAF TDF‐based regimen
93%
Boosted ATV + FTC/TDF(n=402/199)
E/C/F/TDF(n=306/153)
96%
P=0.02
90%
97%P=0.02
92%98%
P=NS
97%
Study 109:Other Outcomes and Summary• Discontinuations due to adverse events
– E/C/F/TAF: 0.9%
• Renal events (n=2), other events (n=7)
– TDF‐based regimen: 2.5%
• Renal events (n=5), other events (n=6)
• Patients who switched to E/C/F/TAF versus TDF‐based regimen were
– Significantly more likely to maintain virologic suppression (P<0.001)
– Significant improvements in spine and hip BMD (P<0.001)
– Significant improvements in proteinuria and other markers of renal function (P<0.001)
Mills T, et al. J Int AIDS Soc. 2015;18(suppl 4):35. Abstract TUAB0102.Permission from Practice Point Communications.
26 © 2015 American Society of Health‐System Pharmacists
Study 112: Switch to E/C/F/TAF in Patients With Renal Impairment
Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35‐36. Abstract TUAB0103.Permission from Practice Point Communications.
Phase 3 study(96 weeks)
Treatment‐experienced
Open‐label
HIV RNA <50 copies/mL
eGFR 30‐69 mL/min
Switch to E/C/F/TAF(n=242)
Primary EndpointWeek 24
Change FromBaseline in eGFR
E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.TAF 10 mg.Pre‐switch ART regimens:
• NRTI: tenofovir DF (65%), abacavir (22%), other (7%), none (5%).• Third agent (some regimens included >1 third agent): PI (44%), NNRTI (42%), INSTI (24%), CCR5 antagonist (3%).
Baseline characteristics:Median age: 58 years.Hypertension/diabetes: 40%/14%.Median CD4: 632 cells/mm3.Median eGFR: 56 mL/min (<60 mL/min: 66%).Dipstick proteinuria grade 1/2/3‐4: 23%/10%/0%.
Study 112: Change in GFR After Switch to E/C/F/TAF in Patients With Renal Impairment
Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35‐36. Abstract TUAB0103.Permission from Practice Point Communications.
Mean Change in eGFR at Week 48(Cockcroft‐Gault)
-6
-4
-2
0
2
4
6
-0.6
AllPatients
Yes
Ch
ang
e in
eG
FR
(m
L/m
in)
No
0.2
-1.8
TDF in Previous Regimen
Actual GFR at Week 24(Iohexol Clearance)
0
10
20
30
40
50
60
70
80
59
AllPatients
Yes
Actual GFR
(ml/min)
No
TDF in Previous Regimen
5863 63
50 49
Baseline
Week 24
56 58 53Baseline eGFR (mL/min):
Study 112: Change in GFR and Other Outcomes After Switch to E/C/F/TAF
• Actual GFR was unaffected by E/C/F/TAF switch, regardless ofprevious regimen
– eGFR remained unchanged through week 48
• Significant improvements after E/C/F/TAF switch (P<0.05)
– Spine and hip bone mineral density
– Urinary tubular proteins and fractional excretion of uric acid
– Albuminuria and proteinuria
– Cholesterol fractions in patients not on a TDF‐based regimen at time of switch
• These 48‐week data support the renal and bone safety of E/C/F/TAF in HIV patients with renal impairment (eGFR 30‐69 mL/min)
Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35‐36. Abstract TUAB0103.Permission from Practice Point Communications.
27© 2015 American Society of Health‐System Pharmacists
U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/guidelines (accessed 2015 April).
Recent Switch Studies: Suppressed
LPV=lopinavir
Trial From To Outcome
GS-123 [1] RAL + TDF/FTC EVG/TDF/FTC/COBI ✔
GS-264[2] EFV/TDF/FTC TDF/FTC/RPV ✔
Strategy-NNRTI[3] NNRTI + TDF/FTC EVG/TDF/FTC/COBI ✔
Strategy-PI[4] PI/r + TDF/FTC EVG/TDF/FTC/COBI ✔
SPIRIT[5] PI/r + 2 NRTI RPV/TDF/FTC ✔
SPIRAL[6] PI/r + 2 NRTI RAL + 2 NRTI ✔
SALT[7] ATV/r + 2 NRTI ATV/r + 3TC ✔
OLE[8] LPV/r + 2 NRTIs LPV/r + 3TC ✔
SWITCHMRK[9] LPV/r + 2 NRTI RAL + 2 NRTI ✗
HARNESS[10] 3rd agent + 2 NRTI RAL+ ATV/r ✗
1. Mills A, et al. HIV Clin Trials. 2014;15:51‐56. 2. Mills A, et al. HIV Clin Trials. 2013;14:216‐223. 3. Pozniak A, et al. Lancet Infect Dis. 2014;14:590‐599. 4. Arribas JR, et al. Lancet Infect Dis. 2014;14:581‐589. 5. Brunetta J, et al. Patient. 2015;[Epub ahead of print]. 6. Martínez E, et al. AIDS. 2010;24:1697‐1707. 7. Perez‐Molina JA, et al. AIDS2014. Abstract LBPE18. 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Eron JJ, et al. Lancet. 2010;375:396‐407. 10. van Lunzen J, et al. AIDS 2014. Abstract LBPE19.
CE IN THE MIDDAY
Hepatitis C Co‐Infection
Jason J. Schafer Pharm.D., M.P.H, BCPS, AAHIVP
Activity Chair
Associate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
28 © 2015 American Society of Health‐System Pharmacists
Patient Case
• MA is a 34 year old woman with HIV/HCV infections diagnosed in 2005
• Never treated for HCV because she refuses to take interferon (IFN)
• She is aware of the new HCV medications and asks if she can be treated
• ART History:– Efavirenz/emtricitabine/tenofovir (2007 – 2009; K103N)
– Raltegravir/emtricitabine/tenofovir (2009 – 2013; reports missing PM doses)
– Elvitegravir/cobicistat/emtricitabine/tenofovir (2013 – present)
• HIV Labs– HIV viral load < 20 copies/mL (x 2 years), CD4 cell count: 550‐650 cells/mm3
• HCV Labs– Genotype 1a, HCV viral load = 3,400,000 copies/mL, Metavir score = 2
• Other Labs– AST = 45 IU/L , ALT = 75 IU/L, SCr = 1.3 mg/dL
How would you approach treating this patient’s HCV infection?
a. Start HCV treatment now
b. Delay HCV treatment until liver disease ismore advanced
c. D/C ART, treat HCV, then restart ART
SVR=sustained virologic response, GT=genotype, DAA=direct acting antivirals, RBV=ribavirin
IFN6 mos
PegIFN/ RBV
12 mos
IFN12 mos
IFN/RBV12 mos
PegIFN12 mos
PegIFN/RBV/DAA
IFN/RBV6 mos
6
16
3442 39
55
70+
0
20
40
60
80
100
DAA Combos
90+
Hepatitis C InfectionTreatment is NOT what it used to be…
SVR Rates for Approved Therapies in HCV GT 1 Patients
1986
1998
2015
2013
1991
2001
MannsM et al. Lancet. 2001; 358:958‐965. Fried MW et al. N Engl J Med. 2002; 347:975‐982. Poordad F et al. N Engl J Med. 2011; 364:1195‐1206. Jacobson IM et al. N Engl J Med. 2011; 364:2405‐2416. Afdhal N et al. N Engl J Med. 2014; 370:1889‐1898.
Feld JJ et al. N Engl J Med. 2014; 370:1594‐603.
29 © 2015 American Society of Health‐System Pharmacists
HIV/HCV Co‐infection
Chung RT et al. N Engl J Med. 2004; 351:451‐9.Torriani FJ et al. N Engl J Med. 2004; 351:438‐450.
Carrat F et al. JAMA. 2004; 292:2839‐48.
Treating Co‐infection is NOT what it used to be…
SV
R (
%)
HCV mono
APRICOT* (n=289)
Ribavic* (n=205)
ACTG 5071* (n=66)
SVR according to genotype for HIV/HCV Co‐infected patients receiving Peg‐interferon plus ribavirin for 48 weeks
80
60
40
20
10
0
42
73
17
44
1429
62
8290
Genotype 1
Genotype 2/3
*80‐85% receiving ART*60‐65% with undetectable HIV RNA
100
Dieterich D et al. CROI 2014; P#24; Rodriguez‐Torres M et al. IDWeek 2013; P#714; Sulkowski M et al. Lancet Infect Dis 2013;13:597–605; Sulkowski M et al. Ann Intern Med 2013;159:86–96; Sulkowski M et al. Lancet 2014;314:653–61; Sulkowski M et al. AIDS. 2014; P#104 LB; Torriani FJ, et al. N Engl J Med. 2004;351:438–50;
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. (accessed 2015 Oct 15).
HIV/HCV Co‐infectionTreating Co‐infection is NOT what it used to be…
100
80
60
40
20
0
SVR (%)
29
14
7
74
89
7463
76
9496
SVR Rates for Approved Therapies in HCV GT 1 Patients Co‐infected with HIV
LDV/SOFIFN+RBV6 mo
PEG12 mo
PEG+RBV12 mo
BOC+PEG+RBV
TVR+PEG+RBV
SMV+PEG+RBV
SOF+PEG+RBV
SOF+RBV OMV/PTV/RTV+DSV+RBV
1986
2013
2004
2015
2014
BOC=boceprivir; TVR=telaprevir; SMV=simeprevir; SOF=sofosbuvir; OMV =ombitasvir; PTV=paritaprevir; DSV=dasabuvir; LDV=ledipasvir
Afdhal N et al. N Engl J Med. 2014; 370: 1889‐98; Afdhal N et al. N Engl J Med. 2014; 370: 1483‐93; Kowdley K et al. N Engl J Med. 2014; 370: 1879‐88; Naggie et al CROI 2015, Oral #LB‐152;
Osinusi A et al. JAMA. 2015; Sulkowski M et al. JAMA. 2015; 313:1223‐1231; Feld JJ et al. N Engl J Med. 2014; 370:1594‐603.
HIV/HCV Co‐infectionSimilar response rates in HCV/HIV co‐infected patients compared to
HCV mono‐infected patients
SVR‐12 (%)
80
60
40
20
10
0
90
100
HCV Monoinfection
HIV/HCV Co‐infection
LDV/SOF x 12 Weeks OMV/PTV/RTV + DSV + RBV x12‐24 Weeks
ION 1,2 3 ION 4,Eradicate
370/385520/538
96%97%91-94%
TURQUOISE‐1
58/63455/473
96%
SAPPHIRE‐1
30© 2015 American Society of Health‐System Pharmacists
Poordad F et al. EASL 2015, Abstract L08; Wyles DL et al. N Engl J Med. 2015; 373:714‐25. Kwo P et al. EASL 2015, Abstract S270; Del Bello DP et al. AASLD 2014, Abstract 994.
HIV/HCV Co‐infectionSimilar response rates in HCV/HIV co‐infected patients compared to
HCV mono‐infected patients
SVR‐12 (%)
80
60
40
20
10
0
90
100
HCV Monoinfection
HIV/HCV Co‐infection
DCV/SOF x 12 Weeks SOF/SIM ± RBV x 12 Weeks
ALLY‐1* ALLY‐3**
ALLY‐2
123/127235/265
96-98%
83-94%92%
Del BelloStudy
11/12150/155
95-97%
OPTOMIST‐1
*ALLY‐1 was conducted in patients with advanced cirrhosis and post‐transplant patients**ALLY‐3 was conducted for genotype 3 patients with and without cirrhosis
HIV/HCV Co‐infection
• HIV co‐infection accelerates fibrosis progressionamong HCV‐infected persons
• Controlling HIV may mitigate progression to some extent, but ART is not a substitute for HCV treatment
• Co‐infected patients have more liver‐related and overall mortality than HCV‐monoinfected patients
• Achieving SVR reduces the incidence of liver relateddeath and improves survival in co‐infected patients
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. (accessed 2015 Oct 15). Lee MH et al. J Infect Dis. 2012; 206:469‐477; Ly KN et al. Ann Intern Med. 2012; 156:271‐8; Ragni MV et al. Haemophilia. 2009; 15:552‐8; Aghemo A et al. Hepatology. 2012;
56:1681‐7.
Delaying HCV Treatment Leads to Liver Disease Progression
HIV/HCV Co‐infection
• CD4+ guided ART interruption was associated with significantly greater riskof disease progression and death compared to continuous ART
– RR 2.5 (95% CI: 1.8‐3.6; p<.001)
• Includes increased CVD, liver, and renal‐related deaths:
El‐Sadr et al. N Engl J Med. 2006; 355:2283‐96.
Stopping ART Can Adversely Affect HIV and
Non‐HIV Related Outcomes
Complications No. of Events Relative Risk
Severe complications
• CVD, liver, renal deaths
• Nonfatal CVD events
• Nonfatal hepatic events
• Nonfatal renal events
114
31
63
14
7
1.5
1.4
1.5
1.4
2.5
With ART Interruption
31 © 2015 American Society of Health‐System Pharmacists
• All co‐infected patients are candidates for HCV therapy
• HIV disease must be stable before initiating HCV treatment
• Interrupting HIV treatment to manage HCV infection is not recommended
• Recommended ART regimens for co‐infected patients are the same as those recommended for patients without HCV
• Co‐infected persons should be treated the same as persons without HIV infection, after recognizing and managinginteractions with antiretroviral medications
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. (accessed 2015 Oct 15).
HIV/HCV Co‐infectionAASLD/IDSA/IAS‐USA Hepatitis C Guidelines
Which HCV treatment strategy do you recommend?
a. Keep ART and start sofosbuvir/ledipasvir
b. Change ART and start sofosbuvir/ledipasvir
c. Keep ART and start daclatasvir + sofosbuvir
d. Change ART and start simeprevir + sofosbuvir
e. Keep ART and startparitaprevir/ritonavir/ombitasvir plusdasabuvir (PrOD)
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C.http://www.hcvguidelines.org. (accessed 2015 Oct 15).
HIV/HCV Co‐infectionRecommended HCV Treatment Regimens in Patients
with or without HIV Co‐infection
Population SMV + SOF LDV/SOF OMV/PTV/RTV + DSV
DCV + SOF
Genotype 1a,no cirrhosis
12 wks± RBV 12 wks 12 wks + RBV 12 wks
Genotype 1a,cirrhosis
24 wks±RBV**
12 wks 24 wks + RBV 24 wks± RBV
Genotype1b,no cirrhosis
12 wks 12 wks 12 wks 12 wks
Genotype1b,cirrhosis
24 wks ± RBV 12 wks 12 wks 24 wks± RBV
**Confirmed absence of Q80K polymorphism
DCV=daclatasvir
32© 2015 American Society of Health‐System Pharmacists
AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C.http://www.hcvguidelines.org. (accessed 2015 Oct 15).
SOF/SMV SOF/LDV SOF/DCV OMV/PTV/RTV + DSV
DRV/RTV/TDF/FTCSMV↑
DRV↔
SOF↑, LDV↑
DRV↔, TDF↑↑
SOF↑, DCV↑,
DRV↔
PTV↓/↑
DRV↓
RAL/TDF/FTCSOF↔, SMV↔
RAL↔
SOF↔, LDV↔
RAL↔, TDF↑
SOF↔, DCV↔
RAL↔
PrOD↔
RAL↑
EVG/COBI/TDF/FTC No dataSOF↑, LDV↑
COBI↑, TDF↑↑
SOF↑DCV – No data
COBI↑
No data
DTG/TDF/FTC No data
SOF – no dataLDV↔
DTG↔, TDF↑
SOF – no data DCV↔
DTG↑
PTV↓
DTG↑
DTG/ABC/3TC No data
SOF – no data LDV↔
ART: No data
SOF – no data DCV↔
DTG↑
PrOD↔
DTG↑
Tenofovir Absorption
Gut Lumen Blood Stream
Tenofovir DF
BCRP
P‐gp
P‐gp
BCRP
ӾLedipasvirRitonavirCobicistat
Enterocytes
BCRP: Breast Cancer Resistance Protein
Custodio J et al. ID Week 2015, Abstract 727.
SOF/SMV SOF/LDV SOF/DCV OMV/PTV/RTV + DSV
EVG/COBI/TAF/FTC No dataSOF↑, LDV↑
COBI↑, TDF↑
SOF↑DCV – No data
COBI↑
No data
HIV/HCV Co‐infectionWhat about TAF??
• TAF is a p‐glycoprotein substrate (like TDF)
• TAF bioavailability increases with cobicistat which increases TFV plasma levels • The TAF dose is adjusted down to 10mg in EVG/COB/TAF/FTC to compensate
• LDV and TAF co‐administration also leads to mild increases in TFV exposure through p‐glycoprotein inhibition.
• Despite increases in TFV with LDV, TFV plasma levels remain much lower with TAF versus TDFand within the range that has not lead to adverse renal effects or bone loss
• E/C/F/TAF may be co‐administered with LDV/SOF without dose modification
33© 2015 American Society of Health‐System Pharmacists
See page 38 for enlarged view
• Drug interaction resources
– AASLD/IDSA/IAS–USA hepatitis C guidelines
– U.S. DHHS Adult and Adolescent HIV guidelines
– www.hiv‐druginteraction.org
– www.hep‐druginteractions.org
Key Takeaways
• Early HIV diagnosis, initiation of ART and engagement in care are essential to achieving long‐term viral suppression.
• Switching ART in response to adverse events can be performed successfully but must be done carefully tomaintain viral suppression.
• Successful treatment of both HIV and HCV in co‐infected patients requires the management ofsignificant drug interactions.
34© 2015 American Society of Health‐System Pharmacists
CDC. http://www.cdc.gov/hiv/pdf/hivtestingalgorithmrecommendation‐final.pdf (accessed 2015 Oct).
CDC and APHL: Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens
CDC and APHL. http://stacks.cdc.gov/view/cdc/23447. Version June 27, 2014.
Perform HIV-1/2 Antigen/Antibody Combination Immunoassay
Perform HIV-1/2 AntibodyDifferentiation Immunoassay
HIV-1 (+)HIV-2 (-)
HIV-1 AntibodiesDetected
HIV-1 (-)HIV-2 (+)
HIV-2 AntibodiesDetected
HIV-1 (+)HIV-2 (+)HIV Antibodies
Detected
HIV-1 (-) or IndeterminateHIV-2 (-)
Perform HIV-1Nucleic Acid Test
AcuteHIV-1 Infection
Negative forHIV-1 Infection
Reactive Nonreactive
Negative for HIV-1 and HIV-2Antibodies and p24Ag
Reactive Nonreactive
HIV-1Infection
HIV-2Infection
DualHIV-1 and HIV-2
Infection
Note: new algorithm may not be uniformly adopted in all settings. If a rapid 3rd generation test is used with a positivie test result, confirmation is needed with a more specific test (eg, Western Blot).
35© 2015 American Society of Health‐System Pharmacists
Adapted from: Fauci AS et al. Ann Intern Med. 1996; 124:654.
Difference in 96‐wk cumulative incidence (97.5% CI)
-20 0-10 10 20
15% (10% to 20%)
7.5% (3.2% to 12%)
7.5% (2.3% to 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors DRV/r
Lennox JL, et al. Ann Intern Med. 2014;161:461‐471.
*Plus TDF/FTC.
ATV/r*RAL*DRV/r*
ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure
1.00
0.75
0.50
0.25
0.00
Cum
ulat
ive
Inci
denc
e
Weeks Since Study Entry
0 24 48 64 80 96 112 128 144
Favors RALFavors RAL
36© 2015 American Society of Health‐System Pharmacists
SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in ART‐Naive Pts to Wk 144
• Open‐label extension, excluding pts with hepatitis B virus (HBV)• Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)
Virologic Success* Virologic Nonresponse No Virologic Data
Pts
(%
)
FavorsEFV/TDF/FTC
95% CI for Difference
0
Wk 48
Wk 96
Wk 144
7.4%
8.0%
8.3%
2.5%
2.3%
2.0% 14.6%
13.8%
12.3%
FavorsDTG + ABC/3TC
15%
8881 80
72 7163
5 6 7 8 107 7
13 1220
30
18
100
80
60
40
20
0
DTG + ABC/3TC QD (n = 414)EFV/TDF/FTC QD (n = 419)
Wk 48 96 144 Wk 48 96 144 Wk 48 96 144
*HIV‐1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.‐10% noninferiority margin.
-15%
Pappa K et al. ICAAC 2014. Abstract H‐647a.
Courtesy of Gilead Sciences
37 © 2015 American Society of Health‐System Pharmacists
Tenofovir Absorption
Gut Lumen Blood Stream
Tenofovir DF
BCRP
P‐gp
P‐gp
BCRP
ӾLedipasvirRitonavirCobicistat
Enterocytes
BCRP: Breast Cancer Resistance Protein
38© 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Self-assessment Questions
The polling questions included in this presentation are listed below as a learner assessment tool.
You may wish to note the correct answers and rationale as you follow along with the speaker.
Patient Case #1
PT is a 37 YO AA female; ER 8/17/15.
5 days abdominal pain, dysuria, foul-smelling urine, vomiting.
Observed overnight, dx pyelonephritis, sent home with oral cephalosporin.
While in observation unit, offered HIV screening per ED protocol.
HIV Antigen(Ag)/Antibody (Ab) 4th-generation enzyme immunoassay (EIA) reactive.
Reports prior negative HIV testing.
New monogamous male sexual partner 6 months ago after 7 years of abstinence. Partner serostatus
unknown.
1. In patients with a reactive 4th-generation HIV Ag/Ab result, what test should be performed next?
a. HIV-1 Western blot.
b. HIV-2 Western blot.
c. HIV viral RNA quantitative assay (viral load).
d. HIV-1/HIV-2 discriminatory immunoassay.
e. CD4 cell count.
2. The HIV-1/HIV-2 differentiation assay (Multispot) results are both non-reactive. What should be
done next for PT?
a. HIV-1 Western blot.
b. CD4 cell count.
c. HIV viral RNA quantitative assay (viral load).
d. Inform the patient that she is definitely infected with HIV.
e. Inform the patient she is definitely not infected with HIV.
39 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
3. PT comes to office 5 days later to learn of confirmed diagnosis. HIV viral load is >10 million copies;
CD4 count is 600 cells/mm3. Should this patient be treated with ART and when?
a. Yes, immediately (today).
b. Yes, in 4 weeks (after genotype available).
c. No, since CD4 count is >500 cells/mm3.
d. Not yet, since she needs time to process her new diagnosis.
e. Not sure.
Patient Case Continued
PT defers treatment at time of diagnosis.
Returns to office one year later.
Asymptomatic.
Viral load 200,000 copies/mL; CD4 600 cells/mm3.
Estimated GFR 110 mL/min/1.73m2.
Takes no other meds.
4. Is treatment with ART recommended for PT?
a. Yes.
b. No.
c. Not sure.
5. Per the DHHS 2015 guidelines, which of the following is currently recommended as a first-line
regimen for this patient?
a. Efavirenz/tenofovir disoproxil/emtricitabine (EFV/TDF/FTC).
b. Rilpivirine/tenofovir disoproxil/emtricitabine (RPV/TDF/FTC).
c. Atazanavir/ritonavir (ATV/r) plus TDF/FTC.
d. Elvitegravir/cobicistat/TDF/FTC (EVG/cobi/TDF/FTC).
e. Darunavir/ritonavir (DRV/r) plus abacavir/lamivudine (ABC/3TC).
40© 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
6. PT starts EVG/c/TDF/FTC. One year later: Viral load undetectable; CD4 count
900 cells/mm3; GFR now 70 mL/min/1.73 m2; HLA B-5701 is positive.
What is the next step?
a. Observe on EVG/c/TDF/FTC until GFR drops below 30 mL/min/1.73 m2.
b. Switch EVG/c/TDF/FTC to Raltegravir (RAL) plus TDF/FTC.
c. Switch EVG/c/TDF/FTC to DTG/ABC/3TC.
d. Switch EVG/c/TDF/FTC to EVG/c/TAF/FTC.
Patient Case #2
MA is a 34 year old woman with HIV/HCV infections diagnosed in 2005
Never treated for HCV because she refuses to take interferon (IFN)
She is aware of the new HCV medications and asks if she can be treated
ART History:
o Efavirenz/emtricitabine/tenofovir (2007 – 2009; K103N)
o Raltegravir/emtricitabine/tenofovir (2009 – 2013; reports missing PM doses)
o Elvitegravir/cobicistat/emtricitabine/tenofovir (2013 – present)
HIV Labs
HIV viral load < 20 copies/mL (x 2 years), CD4 cell count: 550-650 cells/mm3
HCV Labs
Genotype 1a, HCV viral load = 3,400,000 copies/mL, Metavir score = 2
Other Labs
AST = 45 IU/L , ALT = 75 IU/L, SCr = 1.3 mg/dL
7. How would you approach treating this patient’s HCV infection?
a. Start HCV treatment now.
b. Delay HCV treatment until liver disease is more advanced.
c. D/C ART, treat HCV, then restart ART.
41 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
8. Which HCV treatment strategy do you recommend?
a. Keep ART and start sofosbuvir/ledipasvir.
b. Change ART and start sofosbuvir/ledipasvir.
c. Keep ART and start daclatasvir + sofosbuvir.
d. Change ART and start simeprevir + sofosbuvir.
e. Keep ART and start paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD).
42© 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
Abbreviations
HIV Drug Classes
ART antiretroviral therapy
CCR5 C-C chemokine receptor 5
INSTI integrase strand transfer inhibitor
NNRTI nonnucleoside reverse transcriptase inhibitor
NRTI nucleoside (or nucleotide) reverse transcriptase inhibitor
PI protease inhibitor
PI/r ritonavir-boosted protease inhibitor
HIV Drugs
3TC lamivudine
ABC abacavir
ATV atazanavir
ATV/r atazanavir/ritonavir
COBI cobicistat
DRV darunavir
DRV/r darunavir/ritonavir
DTG dolutegravir
EFV efavirenz
EVG elvitegravir
FTC emtricitabine
LPV lopinavir
LPV/r lopinavir/ritonavir
MVC maraviroc
RAL raltegravir
43 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
RPV rilpivarine
RTV ritonavir
TAF tenofovir alafenamide
TDF tenofovir disoproxil
Hepatitis C Virus Drugs
BOC boceprevir
DAA direct-acting antiviral
DCV daclatasvir
DSV dasabuvir
IFN interferon
LDV ledipasvir
OMV ombitasvir
PegIFN peginterferon
PrOD paritaprevir/ritonavir/ombitasvir plus dasabuvir
PTV paritaprevir
RBV ribavirin
SMV simeprevir
SOF sofosbuvir
TVR telaprevir
Miscellaneous
Ab antibody
Ag antigen
EIA enzyme immunoassay
GT genotype
HBV hepatitis B virus
44 © 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
HCV hepatitis C virus
HIV human immunodeficiency virus
NAAT nucleic-acid amplification testing
SVR sustained virologic response
VF virologic failure
VL viral load
45© 2015 American Society of Health‐System Pharmacists
Ongoing Management of the HIV Patient in the Ambulatory Care Setting: Strategies for Achieving Long-term Viral Suppression
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46© 2015 American Society of Health‐System Pharmacists