choosing among current antiretroviral regimens.the relevance of drug–drug interactions and barrier...

Choosing Among Current Antiretroviral Regimens: The Relevance of Drug–Drug Interactions and Barrier to Resistance

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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.


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



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



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


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



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+



Key Interactions: INSTI-Containing ART Regimens Consider www.hiv-druginteractions.org to assist with

identifying potential interactions for all regimens


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



Key Interactions: Boosted PI- or NNRTI-Containing ART Regimens


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.



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


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].



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



Genetic Barrier to Resistance: Recommended INSTI-Based Regimens


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.



Genetic Barrier to Resistance: PI- or NNRTI-Based Regimens


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.



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



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


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].


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.


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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