1. Choosing Among Current Antiretroviral Regimens: The Relevance of Drug–Drug Interactions and Barrier to Resistance
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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.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

4. 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
ART, antiretroviral therapy.
Slide credit: clinicaloptions.com

5. Recommended ART Regimens for Treatment-Naive Pts
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
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BHIVA, British HIV Association; COBI, cobicistat; DHHS, US Department of Health and Human Services; CrCl, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS-USA, International Antiviral Society-USA; LPV, lopinavir; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
*The current EACS guidelines include DRV/RTV or DRV/COBI plus FTC/TDF or FTC/TAF as recommended initial regimens for treatment-naive pts.
References:
1. DHHS Guidelines. July Günthard H, et al. JAMA. 2016;316: BHIVA Guidelines. August EACS Guidelines. October GeSIDA. Enferm Infec Microbiol Clin. 2016;[Epub ahead of print].
Recommended
Alternative
Not included
Slide credit: clinicaloptions.com
References in slidenotes.

6. What Factors Need to Be Considered When Choosing an Initial ART Regimen?
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
ART, antiretroviral therapy; HBV, hepatitis B virus; HBC, hepatitis C virus.
Slide credit: clinicaloptions.com
DHHS Guidelines. July 2016.

7. Initiation of ART: Potential Drug–Drug Interactions
ART, antiretroviral therapy.

8. Older Pts Becoming More Prevalent in the HIV-Infected Population
HIV-infected pts in the HIV clinic at University Hospital, Bonn, Germany
< 50 yrs of age
1200
≥ 50 yrs of age
1000
800
Number of HIV-Infected Pts
600
400
200
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015 Yr
Slide credit: clinicaloptions.com
Presenter communication.

9. Comorbidities Increase With Age and With HIV Infection
No age-related diseases
1 comorbidity
Single-center, case-control study
2 comorbidities
3 comorbidities
4 comorbidities
HIV-Infected Pts (n = 2854)
HIV-Uninfected Controls (n = 8562)
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
100 80 60
Pts (%)
CVD, cardiovascular disease; HTN, hypertension. 40 20
*Comorbidites: bone fractures, CVD, diabetes, HTN, hypothyroidism.
Slide credit: clinicaloptions.com
Guaraldi G, et al. Clin Infect Dis. 2011;53:

10. HIV Pts More Likely to Experience Bone Fractures, CVD, Diabetes, Renal Failure10 20 30 40 60
< 40
41-50
51-60
> 60
Risk (%)
Age (Yrs) 50
Bone Fractures 60
Renal Failure
HIV- 50
HIV+ 40
Risk (%) 30 20 10
< 40
41-50
51-60
> 60
Age (Yrs) 10 20 30 40 60
< 40
41-50
51-60
> 60
Risk (%)
Age (Yrs) 50
Diabetes 10 20 30 40 60
< 40
41-50
51-60
> 60
Risk (%)
Age (Yrs) 50
CVD 10 20 30 40 60
< 40
41-50
51-60
> 60
Risk (%)
Age (Yrs) 50
Hypertension
CVD, cardiovascular disease.
Slide credit: clinicaloptions.com
Guaraldi G, et al. Clinicoecon Outcomes Res. 2013;5:

11. Key Interactions: INSTI-Containing ART Regimens
Consider 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 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
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; COBI, cobicistat; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; HCV, hepatitis C virus; INSTI, integrase strand transfer inhibitor; RAL, raltegravir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate.
References:
DTG/3TC/ABC [package insert]
DTG [package insert]
FTC/TDF [package insert]
FTC/TAF [package insert]
EVG/COBI/FTC/TDF [package insert]
EVG/COBI/FTC/TAF [package insert]
RAL + FTC/TAF [package insert]
RAL + FTC/TDF [package insert]
Slide credit: clinicaloptions.com
References in slidenotes.

12. Key Interactions: Boosted PI- or NNRTI-Containing ART Regimens
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
ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; HCV, hepatitis C virus; PPI, proton pump inhibitor; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate.
References:
ATV [package insert]
DRV [package insert]
Elbasvir/grazoprevir [package insert]
Simeprevir [package insert]
FTC/TDF [package insert]
FTC/TAF [package insert]
RPV/FTC/TDF [package insert]
RPV/FTC/TAF [package insert]
*ATV/RTV only.
Slide credit: clinicaloptions.com
References in slidenotes.

13. Boosting PIs: Cobicistat vs Ritonavir
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]
ATV, atazanavir; DDI, drug–drug interaction; FTC, emtricitabine; COBI, cobicistat; CYP, cytochrome P450; P-gp, P-glycoprotein; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.
1. Gallant JE, et al. J Acquir Immune Defic Syndr. 2015;69:
2. Marzolini C, et al. J Antimicrob Chemother. 2016;71:
3. COBI [package insert]
Slide credit: clinicaloptions.com

14. Initiation of ART: Minimizing the Possibility of Resistance
ART, antiretroviral therapy.

15. 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
ART, antiretroviral therapy; ARV, antiretroviral.
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

16. Genetic Barrier to Resistance for Specific ARVs
DTG
DRV/ RTV
EVG
RAL
3 log
ATV/
RTV
INSTI
(Estimated log change in VL)
Potency
2 log
RPV
NNRTI
FTC
3TC
ABC
TDF
NRTI PI
1 log
3TC, lamivudine; ABC, abacavir; ARV, antiretroviral; ATV, atazanavir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate; VL, viral load. 1 2 3 4
Genetic Barrier to Resistance
(Approximate # Mutations Needed to Fail)
Slide credit: clinicaloptions.com
Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].

17. Genetic Barrier to Resistance: Recommended INSTI-Based Regimens
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/Moderate
Few EVG mutations required for resistance[2]
T66I/A/K
E92Q
S147G
Q148H/R/K
N155H
RAL + FTC/TDF or FTC/TAF
Few RAL mutations required for resistance[2]
Y143C/R/H
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; TPV, tipranavir.
References:
1. DHHS Guidelines. July 2016.
2. Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
*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
References in slidenotes.

18. Genetic Barrier to Resistance: PI- or NNRTI-Based Regimens
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
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
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; TPV, tipranavir.
References:
1. DHHS Guidelines. July 2016.
2. Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
*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
References in slidenotes.

19. 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)
TDR Prevalence,
Resistance to Specific Drugs,
Pts With Virus Predicted to Exhibit Drug Resistance (%) 4 6 8 10
100 2
ABC
TDF
3TC
FTC
AZT
D4T
ETR
NVP
EFV
RPV
ATV
DRV
FPV
NFV
IDV
LPV
SQV
TPV
Any drug class
NRTI
NNRTI PI 12 10 8
TDR in Newly Diagnosed Pts With HIV (%) 6
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; AZT, zidovudine; D4T, stavudine; DRV, darunavir; EFV, efavirenz; ETV, etravirine; FPV, fosamprenavir; FTC, emtricitabine; IDV, indinavir; LPV, lopinavir; NFV, nelfinavir; NVP, nevirapine; RPV, rilpivirine; SQV, saquinavir; TDF, tenofovir disoproxil fumarate; TDR, transmitted drug resistance; TPV, tipranavir. 4 2
High level resistance
Low level/intermediate resistance
Susceptible
Hofstra LM, et al. Clin Infect Dis. 2016;62: SPREAD database. Available at:
Slide credit: clinicaloptions.com

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

21. 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:
2. Jackson H. Nurs Times. 2013;109:21-23.
3. García de Olalla P, et al. J Acquir Immune Defic Syndr. 2002;30:
4. Bangsberg DR, et al. J Antimicrob Chemother. 2004;53:
5. Clutter DS, et al. Infect Genet Evol. 2016;[Epub ahead of print].
Slide credit: clinicaloptions.com

22. 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]
3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; RTV, ritonavir; STR, single tablet regimen; TAF, tenofovir alafenamide fumarate.
1. DHHS Guidelines. July Günthard H, et al. JAMA. 2016;316:
3. ClinicalTrials.gov. NCT
4. DTG/ABC/3TC [package insert]
Slide credit: clinicaloptions.com

23. 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
ART, antiretroviral therapy.
Slide credit: clinicaloptions.com

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