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Choosing Among Current Antiretroviral
Regimens: The Relevance of Drug–Drug
Interactions and Barrier to Resistance
This pro...
Slide credit: clinicaloptions.com
About These Slides
 Please feel free to use, update, and share some or all
of these sli...
Faculty and Disclosure Information
Jürgen K. Rockstroh, MD
Professor of Medicine
University of Bonn
Bonn, Germany
Jürgen K...
Slide credit: clinicaloptions.com
Program Overview
 Key Drug–Drug Interactions With Recommended
First-line ART Regimens a...
Slide credit: clinicaloptions.com
Recommended ART Regimens for
Treatment-Naive Pts
References in slidenotes.
Regimen DHHS[...
Slide credit: clinicaloptions.com
What Factors Need to Be Considered
When Choosing an Initial ART Regimen?
DHHS Guidelines...
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 t...
Comorbidities Increase With Age and With
HIV Infection
 Single-center, case-control study
Slide credit: clinicaloptions.c...
Slide credit: clinicaloptions.com
HIV Pts More Likely to Experience Bone
Fractures, CVD, Diabetes, Renal Failure
Guaraldi ...
Slide credit: clinicaloptions.com
Key Interactions: INSTI-Containing ART
Regimens
 Consider www.hiv-druginteractions.org ...
Slide credit: clinicaloptions.com
Key Interactions: Boosted PI- or NNRTI-
Containing ART Regimens
References in slidenotes...
Slide credit: clinicaloptions.com
Boosting PIs: Cobicistat vs Ritonavir
1. Gallant JE, et al. J Acquir Immune Defic Syndr....
Initiation of ART:
Minimizing the Possibility of
Resistance
Slide credit: clinicaloptions.com
ARV Genetic Barrier to Resistance and the
Emergence of Resistant Mutations
 Drug-resist...
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance for Specific
ARVs
Clutter DS, et al. Infect Genet Evol. 20...
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance:
Recommended INSTI-Based Regimens
References in slidenotes...
Slide credit: clinicaloptions.com
Genetic Barrier to Resistance: PI- or
NNRTI-Based Regimens
References in slidenotes.
Reg...
Slide credit: clinicaloptions.com
Stable Prevalence of Transmitted Drug
Resistance-Associated Mutations in Europe
 SPREAD...
Slide credit: clinicaloptions.com
Causes of Treatment Failure
DHHS Guidelines. July 2016.
Poor adherence
Insufficient drug...
Slide credit: clinicaloptions.com
Risk of Resistance Is Lowest in Adherent
Pts
 Adherence of 90% to 100% necessary to ach...
Slide credit: clinicaloptions.com
What to Choose for Treating Pts With
Adherence Concerns
 For pts with adherence concern...
Slide credit: clinicaloptions.com
Summary
 When choosing an ART regimen, various pt characteristics
need to be considered...
Please take a 2-question survey
by following the link below:
clinicaloptions.com/survey
Go Online for More CCO
Coverage of HIV!
Downloadable audio in which Jürgen K. Rockstroh, MD, provides
narration of these s...
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Choosing Among Current Antiretroviral Regimens.The Relevance of Drug–Drug Interactions and Barrier to Resistance.2016

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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

Published in: Health & Medicine
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Choosing Among Current Antiretroviral Regimens.The Relevance of Drug–Drug Interactions and Barrier to Resistance.2016

  1. 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. 2. Slide credit: clinicaloptions.com About These Slides  Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients  When using our slides, please retain the source attribution:  These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details
  3. 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. 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. 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. 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. 7. Initiation of ART: Potential Drug–Drug Interactions
  8. 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. 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. 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. 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. 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. 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. 14. Initiation of ART: Minimizing the Possibility of Resistance
  15. 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. 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. 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. 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. 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. 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. 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. 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. 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
  24. 24. Please take a 2-question survey by following the link below: clinicaloptions.com/survey
  25. 25. Go Online for More CCO Coverage of HIV! Downloadable audio in which Jürgen K. Rockstroh, MD, provides narration of these slides and discusses relevant case pts and clinical considerations for choosing ART regimens clinicaloptions.com/hiv

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