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Choosing Among Current Antiretroviral Regimens: The Relevance of Drug–Drug Interactions and Barrier to Resistance
This program is supported by an independent educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company)
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Faculty and Disclosure Information
Jürgen K. Rockstroh, MDProfessor of Medicine University of BonnBonn, Germany
Jürgen K. Rockstroh, MD, has disclosed that he has received consulting fees from Abbott, AbbVie, Bristol-Myers Squibb, Cipla, Gilead Sciences, Janssen, Merck, and ViiV; fees for non-CME/CE services received directly from a commercial interest or their agents (eg, speaker bureau) from AbbVie, Gilead Sciences, and Merck; and funds for research support from Gilead Sciences.
Slide credit: clinicaloptions.com
Program Overview
Key Drug–Drug Interactions With Recommended First-line ART Regimens and Impact on Regimen Selection
Genetic Barriers to Resistance of Key Antiretrovirals and Impact on Regimen Selection
Slide credit: clinicaloptions.com
Recommended ART Regimens for Treatment-Naive Pts
References in slidenotes.
Regimen DHHS[1] IAS-USA[2] BHIVA[3] EACS[4] GeSIDA[5]
DTG/3TC/ABC
DTG + FTC/TDF
DTG + FTC/TAF
EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAF
RAL + FTC/TDF
RAL + FTC/TAF
ATV/RTV + FTC/TDF
ATV/RTV + FTC/TAF
DRV/RTV* + FTC/TDF
DRV/RTV* + FTC/TAF
RPV/FTC/TDF
RPV/FTC/TAF
Recommended Alternative Not included
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What Factors Need to Be Considered When Choosing an Initial ART Regimen?
DHHS Guidelines. July 2016.
Pt-Specific Regimen-SpecificBaseline HIV-1 RNA Long-term tolerability and safety
Chronic HBV or HCV coinfection Simplicity
Renal function Food intake requirements (and pt eating habits)
Desire to become pregnant ART interactions with comedications and lifestyle drugs
Illicit drug use ART genetic barrier to resistanceHLA-B*5701 status
Comorbidities and comedicationsResults of genotypic drug resistance
testingAnticipated adherence
Initiation of ART:Potential Drug–Drug Interactions
Slide credit: clinicaloptions.com
Older Pts Becoming More Prevalent in the HIV-Infected Population HIV-infected pts in the HIV clinic at University
Hospital, Bonn, Germany
Presenter communication. Yr
Num
ber o
f H
IV-In
fect
ed P
ts
400
600
800
1000
1200
0
200
1996
1997
1998
1999
2000
2001
2005
2004
2003
2002
2006
2007
2008
2009
2010
2013
2011
2012
2014
2015
< 50 yrs of age≥ 50 yrs of age
Comorbidities Increase With Age and With HIV Infection Single-center, case-control study
Slide credit: clinicaloptions.comGuaraldi G, et al. Clin Infect Dis. 2011;53:1120-1126.
HIV-Infected Pts (n = 2854) HIV-Uninfected Controls (n = 8562)
*Comorbidites: bone fractures, CVD, diabetes, HTN, hypothyroidism.
0
20
40
60
80
100
3 comorbidities4 comorbidities
1 comorbidity2 comorbidities
No age-related diseasesPt
s (%
)
Age, yrs2+ Comorbidities, %
≤ 403.9
41-509.0
51-6020.0
> 6046.9
≤ 400.5
41-501.9
51-606.6
> 6018.7
Slide credit: clinicaloptions.com
HIV Pts More Likely to Experience Bone Fractures, CVD, Diabetes, Renal Failure
Guaraldi G, et al. Clinicoecon Outcomes Res. 2013;5:481-488.
010203040
60
< 40 41-50 51-60 > 60
Ris
k (%
)
Age (Yrs)
50
Bone Fractures
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Ris
k (%
)
Age (Yrs)
50
Diabetes
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Ris
k (%
)
Age (Yrs)
50
CVD
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Ris
k (%
)
50
Renal Failure
Age (Yrs)
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Ris
k (%
)
Age (Yrs)
50
Hypertension
HIV-
HIV+
Slide credit: clinicaloptions.com
Key Interactions: INSTI-Containing ART Regimens Consider www.hiv-druginteractions.org to assist with
identifying potential interactions for all regimens
References in slidenotes.
Regimen Key Drug–Drug Interaction Considerations
All[1-8] Use caution with/avoid polyvalent cation-containing
antacidsDTG/3TC/ABC[1]
DTG + FTC/TDF or FTC/TAF[2-4]
Avoid dofetilide (antiarrhythmic)
Dose adjust metformin (diabetes medication)
EVG/COBI/FTC/TDF[5]
EVG/COBI/FTC/TAF[6]
Avoid lovastatin, simvastatin (lipid-lowering agents), salmeterol (asthma/COPD medication)
Dose adjust metformin
Use caution with hormonal contraceptives
RAL + FTC/TAF or FTC/TAF[7,8] No notable comedications to avoid for RAL aside
from aluminum/magnesium antacids
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Key Interactions: Boosted PI- or NNRTI-Containing ART Regimens
References in slidenotes.
Regimen Key Drug–Drug Interactions
ATV/RTV + FTC/TDF or FTC/TAF[1,3-6]
DRV/RTV + FTC/TDF or FTC/TAF[2,3-6]
Avoid lovastatin, simvastatin, atorvastatin*(lipid-lowering agents), simeprevir, elbasvir/grazoprevir (HCV agents), salmeterol (asthma/COPD medication)
Use caution with/avoid specific antiarrhythmics (eg, amiodarone)
Avoid PPIs (eg, omeprazole) with ATV
Use caution with/avoid specific glucocorticoids (eg, budesonide, fluticasone)
Use caution with hormonal contraceptivesRPV/FTC/TDF[7]
RPV/FTC/TAF[8]
Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone
*ATV/RTV only.
Slide credit: clinicaloptions.com
Boosting PIs: Cobicistat vs Ritonavir
1. Gallant JE, et al. J Acquir Immune Defic Syndr. 2015;69:338-340.2. Marzolini C, et al. J Antimicrob Chemother. 2016;71:1755-1758.3. COBI [package insert]. 2016.
Characteristic Finding
Potency Similar potency associated with ATV/RTV
and ATV/COBI when combined with FTC/TDF[1]
Drug interactions
Both inhibit CYP3A and P-gp[2]
Caution recommended regarding DDIs when switching from RTV to COBI[3]
RTV an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or UGT1A1; COBI is not
Resistance potential RTV has antiviral activity; COBI does not[2]
Initiation of ART:Minimizing the Possibility of
Resistance
Slide credit: clinicaloptions.com
ARV Genetic Barrier to Resistance and the Emergence of Resistant Mutations Drug-resistant HIV-1 mutants emerge during ART due to the combination of:
– Selective pressure of an ART regimen and its genetic barrier to resistance
– Residual replication due to incomplete virologic suppression
Genetic barrier to resistance: the number of HIV-1 mutations required for resistance to an ARV or ART regimen and the frequency at which resistance mutations develop
– Low barrier: 1 mutation → resistance
– Higher barrier: > 1 mutation (accumulation) → resistance
Escape mutants can continue to replicate and develop additional (secondary/compensatory) mutations to:
– Further increase resistance (decrease drug susceptibility)
– Increase viral fitness
Tang MW, et al. Drugs. 2012;72:e1-e25.Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance for Specific ARVs
Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
Genetic Barrier to Resistance(Approximate # Mutations Needed to Fail)
Pote
ncy
(Est
imat
ed lo
g ch
ange
in V
L)
1 log
2 log
3 log
1 2 3 4
EVGRAL
DTG
ATV/RTV
DRV/RTV
ABCTDF
RPVFTC3TC
INSTINNRTINRTIPI
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance: Recommended INSTI-Based Regimens
References in slidenotes.
Regimen Barrier to Resistance
Comments Mutations Highly Reducing
Susceptibility*[2]
DTG/3TC/ABC
DTG + FTC/TDF or FTC/TAFHigh
Resistance to DTG emerges slowly; multiple mutations required for resistance[1,2]
DTG + FTC/TDF or FTC/TAF recommended by DHHS if must treat before resistance results available[1]
--
EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAFLow/
Moderate Few EVG mutations required for
resistance[2]
T66I/A/KE92Q
S147GQ148H/R/K
N155H
RAL + FTC/TDF or FTC/TAF Low/Moderate
Few RAL mutations required for resistance[2]
Y143C/R/HQ148H/R/K
N155H
*NRTI backbone mutations not shown in column: FTC/TDF, M184V/I, K65R, T69ins; ABC/3TC, M184V/I, K65R, L74V/I, T69ins, Y115F, Q151M.
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance: PI- or NNRTI-Based Regimens
References in slidenotes.
Regimen Barrier to Resistance Comments
Mutations Highly Reducing
Susceptibility[2]*
ATV/RTV + FTC/TDF or FTC/TAF High
Fewer ATV/RTV mutations required for resistance vs DRV/RTV[2]
I50LI84VN88S
DRV/RTV + FTC/TDF or FTC/TAF High
Resistance to DRV/RTV emerges slowly[1]
DRV/RTV + FTC/TDF or FTC/TAF recommended by DHHS if must treat before resistance results available[1]
--
RPV/FTC/TDF or FTC/TAF Low Few RPV mutations required for
resistance[2]
L100IK101PE138K
Y181I/VY188L
G190E/QF227CM230L
*NRTI backbone mutations not shown in column: FTC/TDF, M184V/I, K65R, T69ins; ABC/3TC, M184V/I, K65R, L74V/I, T69ins, Y115F, Q151M.
Slide credit: clinicaloptions.com
Stable Prevalence of Transmitted Drug Resistance-Associated Mutations in Europe SPREAD: European HIV surveillance program monitoring TDR in newly
diagnosed, ART-naive pts (current report, N = 9588)
Hofstra LM, et al. Clin Infect Dis. 2016;62:655-663. SPREAD database. Available at: https://spread.crp-sante.lu/.
TDR Prevalence, 2002-2013
0
2
4
6
8
12
2002
-200
5TDR
in N
ewly
Dia
gnos
ed P
ts
With
HIV
(%)
10
2006
-200
7
2008
-201
0
2011
-201
3
Any drug classNRTINNRTIPI
Resistance to Specific Drugs, 2008-2011
Pts
With
Viru
s Pr
edic
ted
to
Exhi
bit D
rug
Res
ista
nce
(%)
4
6
8
10
100
0
2A
BC
TDF
3TC
FTC
AZT
D4T
ETR
NV
PE
FV
RP
V A
TVD
RV
FPV
NFVID
VLP
V
SQ
VTP
V
High level resistanceLow level/intermediate resistanceSusceptible
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Causes of Treatment Failure
DHHS Guidelines. July 2016.
Poor adherence
Insufficient drug level
Viral replication in the presence of drug
Resistant virus
Social/personal issuesRegimen issues
Toxicities
Suboptimal potency
Wrong dose
Host genetics
Poor absorption
Rapid clearancePoor activation
Drug interactions
Treatment failure
Transmission
Slide credit: clinicaloptions.com
Risk of Resistance Is Lowest in Adherent Pts Adherence of 90% to 100% necessary to achieve and
maintain viral suppression[1]
– HIV adherence rates may be as low as 50% to 70%[2]
– Incomplete adherence occurs in all groups of treated individuals[3]
– Lack of adherence to ART a significant predictor of progression to AIDS and death[3]
Risk of resistance is lowest in adherent pts; lack of adherence can lead to lack of viral suppression, exertion of drug selective pressure, and expansion of resistant virus[4,5]
1. Hogg RS, et al. AIDS. 2002;16:1051-1058. 2. Jackson H. Nurs Times. 2013;109:21-23. 3. García de Olalla P, et al. J Acquir Immune Defic Syndr. 2002;30:105-110. 4. Bangsberg DR, et al. J Antimicrob Chemother. 2004;53:696-699.5. Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
Slide credit: clinicaloptions.com
What to Choose for Treating Pts With Adherence Concerns For pts with adherence concerns or for pts in whom treatment is
necessary before drug resistance results available, consider[1,2]:
– DRV/RTV-based regimen
– DTG-based regimen
DRV-based regimens
– No approved STR at present
– DRV/COBI/FTC/TAF STR currently in phase III clinical trial[3]
DTG-based regimens
– If combined with ABC/3TC, contraindicated in HLA-B*5701–positive pts[4]
1. DHHS Guidelines. July 2016. 2. Günthard H, et al. JAMA. 2016;316:191-210.3. ClinicalTrials.gov. NCT02269917.4. DTG/ABC/3TC [package insert]. 2016.
Slide credit: clinicaloptions.com
Summary
When choosing an ART regimen, various pt characteristics need to be considered, including possible drug–drug interactions
By 2020, more than 50% of pts with HIV will be older than 50 yrs of age
Screening for primary transmitted drug resistance recommended prior to ART initiation
A high genetic barrier is particularly attractive in pts with risk of low adherence in order to minimize risk of resistance development
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