In this downloadable slideset, Jürgen K. Rockstroh, MD, reviews how selection of antiretroviral therapy is influenced by drug–drug interactions and differing antiretroviral genetic barriers to resistance. Format: Microsoft PowerPoint (.ppt) File size: 1.17 MB Date posted: 11/4/2016

1. 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)

2. Slide credit: clinicaloptions.com
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3. Faculty and Disclosure Information
Jürgen K. Rockstroh, MD
Professor of Medicine
University of Bonn
Bonn, 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.

4. 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

5. 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

6. Slide credit: clinicaloptions.com
What Factors Need to Be Considered
When Choosing an Initial ART Regimen?
DHHS Guidelines. July 2016.
Pt-Specific Regimen-Specific
Baseline 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 resistance
HLA-B*5701 status
Comorbidities and comedications
Results of genotypic drug resistance
testing
Anticipated adherence

7. Initiation of ART:
Potential Drug–Drug Interactions

8. 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
Numberof
HIV-InfectedPts
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

9. 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 comorbidities
4 comorbidities
1 comorbidity
2 comorbidities
No age-related diseases
Pts(%)
Age, yrs
2+ Comorbidities, %
≤ 40
3.9
41-50
9.0
51-60
20.0
> 60
46.9
≤ 40
0.5
41-50
1.9
51-60
6.6
> 60
18.7

10. 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.
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Risk(%)
Age (Yrs)
50
Bone Fractures
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Risk(%)
Age (Yrs)
50
Diabetes
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Risk(%)
Age (Yrs)
50
CVD
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Risk(%)
50
Renal Failure
Age (Yrs)
0
10
20
30
40
60
< 40 41-50 51-60 > 60
Risk(%)
Age (Yrs)
50
Hypertension
HIV-
HIV+

11. 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
antacids
DTG/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

12. Slide credit: clinicaloptions.com
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 contraceptives
RPV/FTC/TDF[7]
RPV/FTC/TAF[8]
 Avoid PPIs (eg, omeprazole, pantoprazole),
dexamethasone
*ATV/RTV only.

13. 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]

14. Initiation of ART:
Minimizing the Possibility of
Resistance

15. 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].

16. 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)
Potency
(EstimatedlogchangeinVL)
1 log
2 log
3 log
1 2 3 4
EVG
RAL
DTG
ATV/
RTV
DRV/
RTV
ABC
TDF
RPV
FTC
3TC
INSTI
NNRTI
NRTI
PI

17. 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/TAF
High
 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/TAF
Low/Moderat
e
 Few EVG mutations required for
resistance[2]
T66I/A/K
E92Q
S147G
Q148H/R/K
N155H
RAL + FTC/TDF or FTC/TAF
Low/Moderat
e
 Few RAL mutations required for
resistance[2]
Y143C/R/H
Q148H/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.

18. 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]
I50L
I84V
N88S
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]
L100I
K101P
E138K
Y181I/V
Y188L
G190E/Q
F227C
M230L
*NRTI backbone mutations not shown in column: FTC/TDF, M184V/I, K65R, T69ins;
ABC/3TC, M184V/I, K65R, L74V/I, T69ins, Y115F, Q151M.

19. 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
2002-2005
TDRinNewlyDiagnosedPts
WithHIV(%)
10
2006-2007
2008-2010
2011-2013
Any drug class
NRTI
NNRTI
PI
Resistance to Specific Drugs, 2008-2011
PtsWithVirusPredictedto
ExhibitDrugResistance(%) 4
6
8
10
100
0
2
ABC
TDF
3TC
FTC
AZT
D4T
ETR
NVP
EFV
RPV
ATV
DRV
FPV
NFV
IDV
LPV
SQV
TPV
High level resistance
Low level/intermediate resistance
Susceptible

20. Slide credit: clinicaloptions.com
Causes of Treatment Failure
DHHS Guidelines. July 2016.
Poor adherence
Insufficient drug level
Viral replication in the
presence of drug
Resistant virus
Social/personal issues
Regimen issues
Toxicities
Suboptimal
potency
Wrong dose
Host genetics
Poor absorption
Rapid clearance
Poor activation
Drug interactions
Treatment failure
Transmission

21. 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].

22. 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.

23. 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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Downloadable audio in which Jürgen K. Rockstroh, MD, provides
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