ACTIVITY CODE TD342 Antiretroviral Medications What you need to know Jason J Schafer PharmD MPH BCPS AAHIVP Associate Professor Department of Pharmacy Practice ID: 757904
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Slide1
ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals
ACTIVITY CODE
TD342Slide2
Antiretroviral Medications: What you need to know
Jason J. Schafer, PharmD, MPH, BCPS, AAHIVPAssociate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy, Thomas Jefferson UniversitySlide3
Learning Objectives
Upon completion of this presentation, learners should be better able to:Review the life cycle of HIV and the targets for antiretroviral therapy
Describe
the mechanisms of action of
antiretroviral medications for the treatment of HIV infection
Identify factors that influence the choice of antiretroviral therapy in treatment naïve patientsSlide4
Faculty and Planning Committee DisclosuresPlease consult your program book.
I have received grant funding from Merck Pharmaceuticals for investigator initiated research
There
will be no off-label/investigational uses discussed in this presentation.Slide5
What Antiretroviral Therapy to Start
DHHS Guidelines
Recommended Regimens -
2010
Protease
inhibitor
based
Darunavir + ritonavir + emtricitabine + TDF
Atazanavir + ritonavir
+ emtricitabine + TDF
Integrase inhibitor based
Raltegravir + emtricitabine + TDFNNRTI based:Efavirenz + emtricitabine + TDF
A Moving Target
DHHS: Department of Health and Human Services, TDF:
tenofovir
disoproxil
fumarate, NNRTI: non-nucleoside reverse transcriptase inhibitorSlide6
DHHS: Department of Health and Human Services, TDF:
tenofovir disoproxil fumarate, TAF:
tenofovir
alafenamide
DHHS Guidelines Recommended Regimens -
2016
Protease
inhibitor
based
Darunavir
+ ritonavir + emtricitabine + TDFIntegrase inhibitor basedRaltegravir + emtricitabine + TDFElvitegravir + cobicistat + emtricitabine + TDF or TAFDolutegravir + emtricitabine + TDFDolutegravir + abacavir + lamivudine
What Antiretroviral Therapy to Start
A Moving TargetSlide7
What Antiretroviral Therapy to Start
A Moving Target
DHHS: Department of Health and Human Services, TDF:
tenofovir
disoproxil
fumarate, TAF:
tenofovir
alafenamide
a
Lamivudine may substitute for emtricitabine or vice versa.b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.DHHS Guidelines Recommended Regimens - 2018Integrase inhibitor basedRaltegravir + emtricitabinea + TDF or TAFbElvitegravir + cobicistat + emtricitabinea + TDF or TAFb
Dolutegravir +
emtricitabine
a
+ TDF or
TAF
b
Dolutegravir
+ abacavir +
lamivudinea Bictegravir + emtricitabinea + TAFb
US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents. 2017. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/10/initiation-of-antiretroviral-therapy. Accessed March, 2018.Slide8
HIV Life Cycle and Targets
CD4 receptor
CCR5
co-receptor
Glycoprotein 41
Reverse transcriptase enzyme
Nucleos
(t)ide
reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Integrase enzyme
Protease enzyme234561Slide9
Inhibiting Viral Entry
Image adapted
from: Moore JP, et al.
Proc
Natl
Acad
Sci
U S A. 2003;100:10598-10602.
CD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion InhibitorsCD4 Receptor antagonistSlide10
Enfuvirtide
GP41 antagonist, subcutaneous injectionNot recommended as initial therapy
Maraviroc
CCR5 antagonist, tropism test required
Not recommended as initial therapy
Ibalizumab
Humanized monoclonal antibody
Binds to the extracellular
domain of the CD4
+ receptor
Heavily treatment experienced patients
Inhibiting Viral EntryCD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion InhibitorsBrand NameGeneric NameApproval DateFuzeonEnfuvirtide2003SelzentryMaraviroc2007TrogarzoIbalizumab2018Slide11
Blocking Reverse Transcription
Mechanism of action
Structural analogues of nucleoside bases
Competitively
bind to
reverse transcriptase
enzyme
Incorporate
into DNA
chain and terminate DNA
synthesis
Nucleoside Reverse Transcriptase InhibitorsImage adapted from Clavel F. N Engl J Med 2004;350:1023-35.Slide12
Blocking Reverse Transcription
Nucleoside Reverse Transcriptase Inhibitors
Brand Name
Generic Name
Approval
Date
Epivir
Lamivudine (3TC)
1995
Ziagen
Abacavir
(ABC)1998EpzicomAbacavir/lamivudine2004VireadTenofovir disoproxil fumarate (TDF)2001
Vemlidy
Tenofovir
alafenamide
(TAF)
2016
Emtriva
Emtricitabine
(FTC)
2003
Truvada
TDF/
emtricitabine
2004
Descovy
TAF/
emtricitabine
2016
ABC/3TC, TAF/FTC, and TDF/FTC are the
recommended
NRTI combinations
for
use as
initial
therapy.
Recommendations are based on the
potency, durability
, toxicity, and convenience.
Safety is among
the factors to consider when choosing between these drugs.Slide13
Mechanism of action
Non-competitive
binding to reverse transcriptase
Not
analogues of nucleoside bases
Bind
adjacent to
the catalytic
site of enzyme
Blocking Reverse Transcription
Non-Nucleoside Reverse Transcriptase InhibitorsEfavirenzImage adapted from Clavel F. N Engl J Med 2004;350:1023-35.Slide14
Currently recommended as initial regimens only in certain clinical situations for
the following reasons:
Low
genetic barrier for resistance;
Efavirenz
is less well tolerated than the
recommended
regimens; and
Virologic
failure is more common with rilpivirine with high pretreatment viral loads (>100,000 copies/mL) or low CD4 counts (<200 cells/mm3)Blocking Reverse TranscriptionNon-Nucleoside Reverse Transcriptase Inhibitors*Single tablet regimensBrand NameGeneric NameApproval DateSustivaEfavirenz1998Atripla*Efavirenz, emtricitabine, TDF
2006
Edurant
Rilpivirine
2011
Intelence
Etravirine
2012
Complera
*
Rilpivirine
,
emtricitabine
, TDF
2012
Odefsey
*
Rilpivirine
,
emtricitabine
, TAF
2016Slide15
Mechanism of action:
Inhibit insertion of HIV DNA into human DNA following reverse transcription
Blocking Viral DNA Integration
Integrase InhibitorsSlide16
Recommended as initial
treatment for most people with HIV
Agents are generally
well
tolerated
Reports
of insomnia in some
patients
Rare reports of depression
and suicidal ideation, primarily in patients with a history of psychiatric
illnesses
Often better tolerated than comparator agents in clinical trialsBlocking Viral DNA IntegrationIntegrase InhibitorsBrand NameGeneric NameApproval DateIsentress
Raltegravir
2007
Stribild
*
Elvitegravir
,
cobicistat
, TAF, and
emtricitabine
2012
Tivicay
Dolutegravir
2013
Triumeq*
Dolutegravir
,
abacavir
, lamivudine
2014
Genvoya
*
Elvitegravir
,
cobicistat
, TAF, and
emtricitabine
2015
Biktarvy
*
Bictegravir
, TAF and
emtricitabine
2018
*Single tablet regimensSlide17
Mechanism of Action
Bind to protease enzyme prevent cleavage of HIV polyproteins
1. The production of viral polypeptides from mRNA
2. Cleavage of polypeptides
to
form
HIV
proteins
Blocking The Production of Viral Proteins
Protease InhibitorsSlide18
Potent and durable in naive
patients, with a high barrier
to
resistance
Useful for patients at risk for poor
adherence
Less well tolerated than integrase inhibitors in clinical trials
All inhibit CYP3A4,
which may lead to significant drug-drug interactions
Blocking The Production of Viral Proteins
Protease Inhibitors
Brand NameGeneric NameApproval DateNorvirRitonavir1996KaletraLopinavir/ritonavir2000ReyatazAtazanavir2003Prezista
Darunavir
2006
Evotaz
Atazanavir
/
cobicistat
2015
Prezcobix
Darunavir
/
cobicistat
2015Slide19
What Antiretroviral Therapy to Start
How to Choose?
US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents. 2017. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/10/initiation-of-antiretroviral-therapy. Accessed March, 2018.
DHHS: Department of Health and Human Services, TDF:
tenofovir
disoproxil
fumarate, TAF:
tenofovir
alafenamide
a Lamivudine may substitute for emtricitabine or vice versa.b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.DHHS Guidelines Recommended Regimens - 2018Integrase inhibitor based
Raltegravir +
emtricitabine
a
+ TDF or
TAF
b
Elvitegravir + cobicistat +
emtricitabine
a + TDF or TAFbDolutegravir + emtricitabinea + TDF or TAFb
Dolutegravir
+ abacavir +
lamivudine
a
Bictegravir
+
emtricitabine
a
+
TAF
bSlide20
Efficacy
Safety/TolerabilityConvenience/Pill SizeDrug-Drug InteractionsComorbidities/Co-infections
Resistance/Resistance Barrier
Pregnancy
What Antiretroviral Therapy to Start
Influential Factors for the Treatment Naïve PatientSlide21
Audience Response Question 1:
Why are integrase inhibitor based regimens recommended ahead of comparators? A. They more often lead to
virologic
suppression
B. They have fewer drug interactions
C. They are comparably effective, but have better tolerability
D. They have a higher barrier to HIV resistanceSlide22Slide23
Study
Integrase
Agent
Comparator(s)
Follow-up (
Wks
)
Efficacy
STARTMRK
Raltegravir
Efavirenz192 WeeksRaltegravir superior to efavirenzACTG 5257RaltegravirDarunavir/ritonavir Atazanavir/ritonavir96 WeeksRaltegravir superior to darunavir/ritonavirRaltegravir superior to atazanavir/ritonavirGS-102Elvitegravir/cobicistat Efavirenz144 WeeksElvitegravir non-inferior to efavirenz
GS-103
Elvitegravir
/
cobicistat
Atazanavir
/ritonavir
144 Weeks
Elvitegravir
non-inferior to atazanavirWAVESElvitegravir/cobicistat
Atazanavir
/ritonavir
48 Weeks
Elvitegravir
superior
to
atazanavir
/ritonavir
SINGLE
Dolutegravir
Efavirenz
48 Weeks
Dolutegravir
superior
to efavirenz
FLAMINGO
Dolutegravir
Darunavir
/ritonavir
48 Weeks
Dolutegravir
superior
to darunavir/ritonavir
GS-US-380-1489
Bictegravir
Dolutegravir
48
Weeks
Bictegravir
non-inferior to
dolutegravir
GS-US-380-1490
Bictegravir
Dolutegravir
48 Weeks
Bictegravir
non-inferior to
dolutegravir
Antiretroviral Therapy Selection
Integrase Inhibitors and the Comparators – Efficacy and TolerabilitySlide24
Choosing Between The Integrase InhibitorsSlide25
Audience Response Question 2:
Which of the following medications has a significant interaction with all integrase inhibitors?
A. Omeprazole
B. Simvastatin
C.
Metformin
D.
MultivitaminsSlide26Slide27
Drug
Substrate
Inhibits
Induces
Raltegravir
UGT
Elvitegravir
/Cobi
3A4
3A4,
Pgp
, MATE-12C9
Dolutegravir
UGT, 3A4
MATE-1, OCT-2
Bictegravir
UGT, 3A4
MATE-1, OCT-2
Absorption
INSTIs are not negatively impacted by the concurrent use of proton pump inhibitors or H2-blockers
INSTs are negatively impacted by divalent and trivalent
cations
in
antacids
and
multivitamins
through chelation interactions
Metabolism
Raltegravir
has the least interactions
Dolutegravir
and
bictegravir
have some CYP3A4 metabolism and therefore few drug interactions
Elvitegravir
has many interactions due to CYP3A4 metabolism and
cobicistat
boosting
Drug
Recommendation with Al, Mg
Containing Antacids
Raltegravir
Do not co-administer with Al-Mg antacids
Elvitegravir
Separate
by ≥ 2 hours
Dolutegravir
Administer DOL 2 hours prior or 6 hours after antacid
Bictegravair
Separate
by ≥ 2 hours
Antiretroviral Therapy Selection
Choosing Between The Integrase Inhibitors – Drug-Drug InteractionsSlide28
Cobicistat
and low-dose ritonavir are
used
to increase bioavailability and prolong t
½ of
elvitegravir
and protease inhibitors
Activity
primarily via
Pgp
inhibition and CYP 3A4 inhibition in the liver and GI tract Achieves higher and sustained troughs that limit the possibility of suboptimal levelsAntiretroviral Therapy SelectionChoosing Between The Integrase Inhibitors – BoostingSlide29
Elimination
Cobicistat is an inhibitor of MATE-1 and therefore, inhibit active tubular secretion of creatinine
SCr
increases by ~10% within 1-2 weeks and plateaus
Dolutegravir
is an inhibitor of OCT2 and MATE-1 and can also inhibit active tubular secretion of creatinine
SCr
increases by
~10% within
1-2 weeks and plateaus
Metformin is eliminated through OCT2 and MATE-1
AUC increase of 79% with dolutegravirAUC increase of 39% with bictegravirDofetilide is eliminated through OCT2 and MATE-1Contraindicated with dolutegravir and bictegravirAntiretroviral Therapy SelectionChoosing Between The Integrase Inhibitors – Drug-Drug InteractionsDolutegravirBictegravirDolutegravirBictegravir CobicistatSlide30
Tenofovir
alafenamide (TAF) is a prodrug with 91% less circulating plasma tenofovir
TAF
reduces
the risk of kidney injury and
BMD losses
in comparison to TDF
Antiretroviral Therapy Selection
Choosing Between NRTIs – TDF or TAF?
Tenofovir
disoproxil fumarate (TDF) is a prodrug converted to tenofovir in the plasma and then enters the HIV target cell. TDF can lead to diminished renal function and losses in bone mineral density (BMD)Image adapted from Babusis D, et al. Mol Pharm. 2013;10(2):102:459-466Slide31
Incidence = 5-8%Onset - within 6 weeks of initiating treatment
Multi-organ system syndrome with symptoms from ≥ 2 of the following:Fever, rash, GI (nausea, vomiting, diarrhea or abdominal pain), malaise/fatigue, respiratory (cough or dyspnea)Can be fatal upon re-challenge
HLA-B*5701 test has a 100% negative predictive value
Antiretroviral Therapy Selection
Choosing Between NRTIs –
Abacavir
Hypersensitivity
Mallal, et al. N Engl J Med 2008;358:568-79Slide32
Antiretroviral Therapy Selection
Choosing Between NRTIs –
Abacavir
and Cardiovascular Disease Risk
Study
Study Design
Event (n)
Patients (n)
Abacavir
Effect
Risk of MI (95% CI)
D:A:DCohortMI (387)22,625Yes1.70 (1.17-2.47)D:A:D 2013CohortMI (493)32,663Yes1.47SMARTRCT
MI (19)
2,752
Yes
4.30 (1.40-13.0)
Danish
Cohort
MI (67)
2,952
Yes
2.00 (1.07-3.76)
VA
Cohort
CV event (501)
10,931
Yes
1.64 (0.88-3.08)
NA-ACCORD
Cohort
MI (301)
16,733
Yes
1.33
Swiss
Cohort
CVD event (350)
11,625
Yes
3.36
(2.04-5.53)
Swiss HIV Cohort
Cohort
CVD event
(365)
11,856
Yes
2.06 (1.43-2.98)Slide33
Antiretroviral Therapy Selection
Choosing Between NRTIs –
Abacavir
and Cardiovascular Disease Risk
Study
Study Design
Event (n)
Patients (n)
Abacavir
Effect
Risk of MI (95% CI)
French DatabaseCCMI (289)74,958No*1.27 (0.64-2.46)ALLRT/ACTGCohortMI (36)5,056No0.70 (0.20-2.40)GSK Meta-analysis of RCTs
MI (27)
14,174
No
0.17 (0.10-0.27)
VA Case Registry
Cohort
MI (278)
19,424
No
1.18 (0.92-1.50)
FDA
Meta-analysis
of RCTs
MI (24)
9,868
No
1.02
(0.56-1.84)
*Without adjustment for cocaine use OR: 2.01 (1.11-3.64
)Slide34
When selecting a regimen, a number of patient and regimen specific characteristic should be considered
The goal is to provide a potent, safe, tolerable, and easy to adhere to regimen for the patient in order to achieve sustained
virologic
control
CVD is one of several specific comorbidities listed among those to consider
“In patients with high cardiac risk, consider avoiding
abacavir
containing regimens”
Associated with increased cardiovascular risk in some…but not all studies
Antiretroviral Therapy Selection
Choosing Between NRTIs –
Abacavir and Cardiovascular Disease RiskUS DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents. 2017. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/10/initiation-of-antiretroviral-therapy. Accessed March, 2018.Slide35
Summary
Currently there are six targets for antiretroviral therapy agents within the HIV life cycleThese agents differ in terms of efficacy, tolerability, safety, durability and their potential for drug-drug interactions
All of these factors must be considered when selecting antiretroviral therapy for patients living with HIVSlide36
Antiretroviral Medications: What you need to know
Jason J. Schafer, PharmD, MPH, BCPS, AAHIVPAssociate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy, Thomas Jefferson UniversitySlide37
ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals
ACTIVITY
CODE
TD342